Role of myeloid-derived suppressor cells in tumor recurrence

Kathryn Cole; Zaid Al-Kadhimi; James E Talmadge

doi:10.1007/s10555-023-10079-1

. 2023 Jan 14;42(1):113–142. doi: 10.1007/s10555-023-10079-1

Role of myeloid-derived suppressor cells in tumor recurrence

Kathryn Cole ¹, Zaid Al-Kadhimi ^1,³, James E Talmadge ^1,^2,^3,^✉

PMCID: PMC9840433 PMID: 36640224

Abstract

The establishment of primary tumor cells in distant organs, termed metastasis, is the principal cause of cancer mortality and is a crucial therapeutic target in oncology. Thus, it is critical to establish a better understanding of metastatic progression for the future development of improved therapeutic approaches. Indeed, such development requires insight into the timing of tumor cell dissemination and seeding of distant organs resulting in occult lesions. Following dissemination of tumor cells from the primary tumor, they can reside in niches in distant organs for years or decades, following which they can emerge as an overt metastasis. This timeline of metastatic dormancy is regulated by interactions between the tumor, its microenvironment, angiogenesis, and tumor antigen-specific T-cell responses. An improved understanding of the mechanisms and interactions responsible for immune evasion and tumor cell release from dormancy would help identify and aid in the development of novel targeted therapeutics. One such mediator of dormancy is myeloid derived suppressor cells (MDSC), whose number in the peripheral blood (PB) or infiltrating tumors has been associated with cancer stage, grade, patient survival, and metastasis in a broad range of tumor pathologies. Thus, extensive studies have revealed a role for MDSCs in tumor escape from adoptive and innate immune responses, facilitating tumor progression and metastasis; however, few studies have considered their role in dormancy. We have posited that MDSCs may regulate disseminated tumor cells resulting in resurgence of senescent tumor cells. In this review, we discuss clinical studies that address mechanisms of tumor recurrence including from dormancy, the role of MDSCs in their escape from dormancy during recurrence, the development of occult metastases, and the potential for MDSC inhibition as an approach to prolong the survival of patients with advanced malignancies. We stress that assessing the impact of therapies on MDSCs versus other cellular targets is challenging within the multimodality interventions required clinically.

Keywords: Myeloid-derived suppressor cells, Metastasis, Dormancy, Circulating tumor cells, Pre-metastatic niche

Introduction

When possible, solid tumors are treated with surgery at diagnosis. However, despite resection of the primary tumor, many patients have disseminated tumor cells (DTCs) at diagnosis. Over time, these DTCs become clinically or radiologically detectable as metastatic disease. Further, the majority of patients has detectable metastatic disease at diagnosis or later becomes refractory to intervention. In recent decades, screening programs have resulted in earlier detection and treatment for patients with breast, colorectal, and prostate cancers [1, 2]. This has contributed to significant improvement in 5- and 10-year overall survival (OS) rates. In addition, new molecular targeted and immune therapies together with conventional treatments have improved the OS of these and other types of solid tumors [3, 4]. However, the fatal outcomes for patients with metastatic disease have not changed. In recent years, research [5–7] has focused on DTCs, which are also known as “minimal residual disease” (MRD), as the origin for clinically overt metastases. The biology of MRD is different relative to that of primary tumors. These lesions often arise following prolonged dormancy and later “awaken” in response to intrinsic and/or tissue specific factors, somatic and therapeutic pressure-induced mutations, and therapeutic resistance. Thus, an improved understanding of the mechanisms underlying the biology of tumor cell release from dormancy is critical to prevent the progression of detectable metastatic disease. Immune surveillance is hypothesized to be one of the principal mechanisms of DTC dormancy and is associated with tumor cell arrest in the G0–G1 state. [8, 9] As such, one clinical goal is to identify and develop novel therapeutic strategies targeting the eradication of dormant DTCs or maintaining them in an G0–G1 state. [10]

During tumor progression, the invasion and metastasis of tumor cells to distant organs can progress to overt metastases resulting in patient mortality. Clinically, it is well established that overt metastases are associated with poor patient outcomes [11]. However, many patients with no detectable metastases at diagnosis and curative surgery can later develop overt metastases months, years, or even decades later [12]. This latency period, during which cancer cells do not grow and remain in a quiescent or equilibrium state, is known as “cancer dormancy” [13]. In these patients, DTCs can remain in a latent state as micro-metastases, designated as “dormant metastases” for variable durations among tumors [14]. The theory of occult tumors as dormant metastatic lesions in different solid tumors is well-founded [15], dating back to the 1930s if not earlier. [16, 17] In 1934, Australian pathologist Rupert Willis used the concept of DTC dormancy to explain recurrent metastases that occurred long after treatment of a patient’s primary disease. [18]

Although the concept of dormancy is relatively old, our biological and molecular understanding of this process and the mechanism of cellular release from dormancy is not fully understood. In 1954, Geoffrey Hadfield postulated that tumors that recurred years post excision at a metastatic site must have arisen from DTCs. Further, these DTCs were held in mitotic arrest, which led him to coin the term “dormant cancer cell” [19]. Multiple, independent lines of evidence support the concept that dormancy is the biological mechanism contributing to relapse. One is the finding that DTCs can be found in bone marrows (BM) of cancer patients at the time of their primary tumor resection [20, 21]. Additionally, examples of DTC dormancy have come from organ transplantation studies, in which inadvertent transfer of malignant cells occurred between an organ donor and a recipient, even though the donors were believed to be cured up to a decade prior to transplantation. [22] Melanoma is one example [7, 23]. Notably, the origin of these metastases could be traced back to the donors, revealing that the transplanted organs harbored ~ 15-year-old dormant DTCs that were able to resume proliferation once established in a favorable environment such as immunosuppression. This observation also provided support for a major role of the host immune system in regulating the dormancy colonization switch.

There are two overall mechanisms of dormancy: quiescence and tumor mass dormancy (Fig. 1). Quiescence is a state of dormancy in which tumor cells do not proliferate and are maintained by interactions with the extracellular matrix in pre-metastatic niches, hypoxia, and endoplasmic reticulum stress [24]. Experimental evidence suggest that cellular dormancy or quiescence, as defined by Hadfield and further explored by the Ann Chambers’ group [15], occurs where tumor cells enter a state of mitotic arrest as solitary cells. This contrasts with micrometastatic dormancy, which occurs at the metastatic tumor mass level and not at a cellular level. In this mechanism of dormancy, cells are proliferative but undergo apoptosis at a similar rate and thus maintain a mass constant. Support for this mechanism of DTC dormancy was provided by studies from the laboratory of Dr. Folkman. They showed that despite being mitotically active, the tumor mass does not progress due to failure in angiogenesis [25, 26]. Another line of support was provided by the laboratory of Dr. Chambers, who observed that some liver micro-metastases do not progress to macro-metastases [15]. Besides angiogenesis, immune-related mechanisms may also maintain the tumor mass in a state of “equilibrium,” which is associated with dormancy when proliferative cells are found but do not progress into larger lesions. These immune-related mechanism have been shown in both the settings of primary and metastatic tumors [27, 28]. Thus, micro-metastatic dormancy can be categorized into angiogenic dormancy and immunologic dormancy. As different as these categories are, they can all contribute to clinical latency. In addition, it is possible that both mechanisms may coexist and are not mutually exclusive in cancer patients.

Timing and processes of tumor metastasis initiation and progression

Metastasis is initiated when tumor cells leave the primary tumor and enter the hematopoietic or lymphatic system as circulating tumor cells (CTCs) or invade through tissue adjacent to the primary tumor. However, the formation of a clinically relevant metastasis occurs following survival of CTCs during innate immune cell interactions, as well as vascular turbulence, vascular arrest, and extravasation. The arrest of CTCs is a mechanical process such that the survival and proliferation of arrested tumor cells are, in part, capillary bed selective, as varying tumor cell phenotypes preferentially become established in distinct secondary organs [29]. Thus, vascular and lymphatic circulation has an important role in the dissemination and arrest of tumor cells. As such, the arrest of tumor cells in a given organ is a necessary but insufficient portion of the process for the initiation of a metastasis [30]. For example, breast adenocarcinoma metastases are frequently initially found in axillary lymph nodes, from which they then traffic to the liver, lungs, bones, and, lastly, brain, supporting a progression of lymphatic followed by hematogenous metastatic spread [31, 32]. Similarly, lung cancers initially metastasize to the regional lymph nodes, other secondary sites, and then to the brain [31, 33]. Thus, when CTCs survive arrest, they may proliferate, become vascularized, and progress into DTCs [34]. However, due to selective pressures, the presence of CTCs and DTCs is, again, not predictive of the extent of overt metastasis [35], as most tumor cells that enter the circulation are rapidly eliminated [36]. Clinically, CTCs can be used to stratify breast, prostate, and colorectal cancer patients to monitor disease progression and provide a prognostic tool [37] for PFS and OS [38]. The hypothesis that specific organ microenvironments support secondary tumor foci by providing congenial “soils” integral to metastasis formation was first published by Paget. These “soils” contributed to site specificity and establishment of an appropriate microenvironment to support tumor seeding [32]. Thus, the selection of metastatic sites is not random but rather due to various affinities of tumor cells for the milieu of specific organs.

The heterogeneity of metastatic lesions is associated, in part, with the progression of cells within early DTCs rather than progression from primary tumors: a process known as parallel progression [39–41]. The circulation and arrest of CTCs early in tumor progression are supported by the finding that DTCs are detected in the BM of patients with early-stage breast cancer [42], including patients with pre-invasive ductal carcinoma in situ (DCIS) [43, 44]. Several studies comparing the genotypes of DTCs with those of primary tumor cells have shown that DTCs can be less evolved than cells in a primary tumor [45]. This supports the process of parallel evolution with DTCs arising earlier than the majority of primary tumor cells [39, 45–47]. For example, in breast cancer patients, BM DTCs display fewer chromosomal aberrations, sub-chromosomal allelic losses, and gene amplification events than cells from primary tumors, as documented by comparative genomic hybridization [48]. Indeed, only half of BM DTCs display abnormal karyograms, as opposed to 100% of cells from primary tumors [48, 49]. This divergent molecular progression between primary tumors and DTCs supports a prolonged time frame between CTC arrest, formation of an overt metastasis, and diagnosis of a primary tumor. Furthermore, parallel evolution is supported by microarray studies of primary tumors, including breast tumors, with the identification of expression profiles predicting the risk of developing a metastasis [49–51]. These microarray studies also suggested that DTCs and micro-metastases occurred years before diagnosis.

The above studies on parallel evolution have been confirmed and extended with studies using tumors from colorectal carcinoma (CRC) patients. In these CRC studies, tumor cells in early-stage cancer patients were shown to have established a subset of primary tumor cells with invasive potential [52]. Genetic mapping of clonal and sub-clonal tumor cell progression, with whole-exome sequencing of 23 metastatic CRC patients, showed [53] that most single-nucleotide variants were shared between the primary tumor and metastases despite their phenotypic and functional differences. Another study undertaking a phylogenetic analysis of CRC progression documented the divergence of metastatic lineages occurring early in cancer progression [54], supporting the origin of metastatic cells from one founder cell. This suggests that in most patients, a metastatic lesion maybe derived from a single tumor cell before it is clinically detectable. In addition, it has been reported that the primary tumors of ~ 90% of patients with metastatic CRC have a sub-clonal selection of tumor cells with a selective growth advantage. Together, studies such as these have demonstrate that parallel evolution of primary and secondary tumors occurs in association with host selection pressures [55] and that metastasis occurs early during tumor progression, frequently long before diagnosis [50, 56].

MDSCs and metastasis

Cancer patients who present with a high tumor burden and/or an advanced clinical stage or histologic grade frequently have an increase in circulating myelopoietic progenitor cells (MPCs) and neutrophils (termed neutrophilia [57, 58]) in their PB [59, 60]. Cancer-associated neutrophilia and the associated circulating MPCs are due in part to tumor secretion [57] of hematopoietic growth factors, including colony-stimulating factors (CSFs) [61]. CSFs stimulate the proliferation and mobilization of MPCs from the BM into the circulation [62, 63]. Mobilized MPCs can establish sites of extramedullary myelopoiesis (EMM) in the spleen or liver, further increasing the frequency of circulating MPCs and neutrophilia.

A subset of circulating and tumor infiltrating MPCs are identified as MDSCs due to their innate immune suppressive activity [64, 65]. Currently, there are three recognized subsets of MDSCs [66–68]: granulocytic (G) or polymorphonuclear (PMN), monocytic (M), and immature or early (i or e). The comparative human phenotype remains somewhat controversial; however, at present, most investigators agree that human MDSCs are lineage-negative (Lin⁻), i.e., lacking T-(CD3), B-(CD19/CD20), and natural killer (NK)-(CD56) cell markers and are CD11b⁺CD33⁺HLA-DR^−/low69. These MDSC subsets are differentiated based on their expression of the granulocyte marker CD15 or CD66b, the monocyte marker CD14, and CD33. The third MDSC subset (i-MDSC) lacks markers for granulocytes and monocytes.

MDSCs contribute to immune evasion by inducing T-cell dysfunction through the production of reactive oxygen species (ROS) [70, 71], arginase-1 (ARG1) [72], and nitric oxide synthase (NOS2) [73]. ARG1 hydrolyzes extracellular L-arginine into urea and ornithine [74]. L-arginine is required for T-cell proliferation [72], cytokine production [72] and expression of the T-cell receptor zeta chain (TCR- ζ) [72]. Thus, depletion of extracellular L-arginine inhibits T-cell proliferation, function, reduces anti-tumor activity [75–78], and potentially induces cell cycle arrest [79]. Thus, the downregulation of TCR- ζ chain expression in T-cells is associated with reduced stability of TCR-ζ mRNA [80],which may also contribute to the inhibition of T-cell proliferation [81]. Further, L-arginine is a substrate for inducible (i)-NOS [74], which results in the production of nitric oxide (NO), a potent signaling molecule with lymphotoxic activity [82]. iNOS also contributes to MDSC immunosuppression by increasing signal transducer and activator of transcription 3 (STAT3) activation, elevating ROS levels via the production of NO [83–85], contributing to the formation of peroxynitrites via interaction between NO and ROS [85, 86] and results in nitrosylation of T-cell receptors [87–90]. As such L-arginine has a role in two mechanisms of immunosuppression, ARG1 and iNOS. In addition, MDSCs can secrete immunosuppressive cytokines, most notably IL-10 [91], which also contribute to the immunosuppressive activity of MDSCs.

MDSCs have been shown to have a role in the process of tumor metastases by suppressing the immune system [92], contributing to vasculogenesis [93], and possibly aiding in the formation of a pre-metastatic niche [94]. A pre-metastatic niche provides a microenvironment consisting of infiltrating inflammatory cells and extracellular matrix proteins that facilitate metastatic cell colonization via the arrest of CTCs and survival of DTC [95]. Steven Paget stated that metastasizing tumor cells have site-specific preferences in association with the presence of congenial soil such that specific tumor types “seed” to specific organs [32], a concept that predates and provides a perhaps more accurate mechanism relative to the concept of a pre-metastatic niche based on the timing of tumor progression. Paget posited in this “seed-and-soil” hypothesis that the spread of tumor cells was not random but rather governed by a regulated process [32]. This hypothesis was elaborated on by Kaplan et al., who observed that a pre-metastatic niche was supported by vascular endothelial growth factor receptor-1 positive (VEGFR1⁺) BM-derived hematopoietic progenitor cells [94], a cell population now known as MDSCs. MDSCs promote and sustain tumor angiogenesis primarily by the secretion of matrix metalloproteinases (MMPs). Mechanistically, MMP-9 can boost angiogenesis and stimulate tumor neovasculature by increasing the bioavailability of VEGF [96]. This initiates a positive feedback loop as VEGF can also trigger MDSC recruitment [97]. The accumulation of tumor-infiltrating MDSCs has also been shown to correlate with intra-tumoral VEGF concentration during tumor progression [98].

MDSCs are also associated with myelopoiesis, which is frequently dysregulated in cancer patients and is associated with failure of immature myeloid cells to differentiate. This creates a source of immature myeloid cells in the BM that can be mobilized into the circulation with MPCs, arresting in organs that are common sites of metastasis. Hematopoietic progenitor cell (HPC) mobilization occurs through tumor secretion of growth factors, such as granulocyte-colony stimulating factor (G-CSF), or disruption of CXC chemokine receptor 4 (CXCR4) [99] binding to its ligand, stromal cell-derived factor 1 (SDF-1/CXCL12). CXCR4 is expressed on CD34⁺HPC and, when bound to its ligand CXCL12, inhibits CD34⁺ HPC mobilization [99]. G-CSF induces progenitor cell mobilization and secretion of proteases that can cleave CXCR4 [100], making it unable to bind to its ligand (CXCL12) contributing to MPC mobilization [100]. In cancer patients, this presents clinically as neutrophilia and monocytosis. Further, the administration of myelopoietic growth factors in both cancer patients and normal stem cell donors [101] has been shown to increase the serum levels of the stromal factor MMP-9. MMP-9 supports MDSC migration through the bone marrow [102, 103], as well as tumor progression [104–106]. Circulating MDSCs can then arrest in secondary lymphoid tissues, such as the spleen or liver, and proliferate, i.e., EMM.

Indeed, increased frequencies of myeloid (CD33⁺) and hematopoietic progenitor (CD34⁺) cells have been found in the spleen of cancer patients with solid tumors as compared to patients without neoplastic disease [107, 108]. Furthermore, the frequencies of myeloid and MPPs cells in the spleen of cancer patients negatively correlate with OS [108]. Though rare, patients with solid tumors can develop an enlarged spleen [109] (splenomegaly). Splenomegaly is caused by increased EMM [110], which can also occur in the liver [111, 112] following dysregulation of the BM microenvironment [113]. Perturbation of the BM microenvironment during tumor progression, metastasis, and/or chemotherapy can also result in myelofibrosis (MF). This is supported by a case report by Kiely et al. [110], in which six out of eight patients with metastatic carcinoma experienced bone pain and marrow fibrosis [110]. Similarly, BM metastases secondary to MF have also been observed in a breast cancer patient [114]. Recent studies have supported this observation with the finding that pulmonary fibrosis has a pathobiology similar to MDSCs in cancer [115] based on a common role for CXCR2 in tumor-associated increase in MDSCs [116]. In the bleomycin model of pulmonary fibrosis, G-MDSCs have been shown to have a key role in the development of pulmonary hypertension via regulation by CXCR2 [117], an observation that has been extended to patients with idiopathic pulmonary fibrosis that includes increase in PB G-MDSCs via expression of CXCR2. Studies such as these provide an insight into tumor growth regulation and immune dysregulation in the marrow resulting in increased myelopoiesis and MDSC frequencies that can further neoplastic progression and contribute to niche formation.

Dormancy of micro-metastatic foci

Consistent with the chronology of metastasis and parallel evolution is the finding that DTCs can become dormant, a state in which they survive while not increasing in size, allowing DTCs to remain undiagnosed for years or even decades [18]. However, following release from dormancy, DTCs proliferate, forming overt metastatic foci. Quiescent dormancy has been additionally supported by a meta-analysis with over 60,000 early-stage breast cancer patients given endocrine therapy and documenting that metastases become detectable 5 to 20 years following primary tumor diagnosis, surgical resection, and adjuvant chemotherapy [118]. However, the relative contribution of quiescent DTC and their progression into micro-metastases in relation to cancer relapse and survival, relative to chemo-resistance or other treatment challenges, remains unclear.

The second mechanism of dormancy, termed tumor mass dormancy [24, 28], occurs when balance is achieved between tumor cell proliferation and death, generating a “steady state” in which the DTC size remains constant [25]. This balance is achieved by angiogenic or immune-mediated regulation. The former is due to the requirement for growth of cancer cells of energy resources, which is provided by vascularity [119]. Angiogenesis, the process by which additional blood supply (vascularity) is developed, is regulated by pro-angiogenic and anti-angiogenic factors [120]. By regulating the tumor vascular supply, these factors affect the transport of oxygen and nutrients to the tumor site, supporting tumor growth and reducing apoptosis [121]. Thus, there may be a trigger for DTC re-emergence that occurs in patients who develop metastases that do not occur in others. Physiological stresses that induce neoangiogenesis such as systemic inflammation or surgery could cause dormant cells to re-enter the cell cycle. This occurrence has been supported by a retrospective study showing that early breast cancer relapse incidents during the 9- to 18-month period after surgery are reduced approximately fivefold in patients taking preoperative nonsteroidal anti-inflammatory drugs [122], suggesting that systemic inflammation is indeed a trigger.

Immune-mediated tumor mass dormancy can also control the development and growth of dormant tumor lesions. Thus, the survival and continued growth of primary and secondary tumor foci requires the evasion of the host immune response [123, 124]. This mechanism of dormancy is evoked when the rate at which immune-mediated cancer cell cytotoxicity equals cancer cell proliferation, resulting in a malignant mass with a stable size [125]. Immune-mediated dormancy is suggested to be the result of tumor-specific cytostatic and cytolytic CD8⁺ T-effect or cell activity [126]. However, T-cell responses that can cause dormancy can also lead to secretion of cytokines that inhibit angiogenesis [127, 128]; which would then lead to angiogenic dormancy. This response suggests the potential for crosstalk between these two dormancy mechanisms.

MDSCs, pre-metastatic niches, and release from metastatic dormancy

The microenvironment of metastatic lesions can contribute to the formation of DTCs by supporting tumor cell survival and proliferation [34] and may be recognized as metastatic niches [129]. These niches can contribute to metastatic site specificity due to conditioning by organ-specific secretion of growth factors and hormones that support the growth/survival of tumor cells in a tumor- and organ-specific manner and by the systemic expansion of and infiltration by tumor-associated macrophages (TAM), neutrophils, T-regulatory (T-reg) cells, and MDSCs [130]. These leukocytes originate from the BM where they can be found in high numbers, as well as from extramedullary sites of hematopoiesis [131]. This supports in part why bone is a common site for DTCs. Prior to or following CTC arrest, a metastatic niche can provide functional elements critical to tumor cell survival and proliferation, including vascularization, modification of the extracellular matrix (ECM), recruitment and infiltration of MPCs, establishment of hypoxia, and organ-associated epithelial cell secretion of hormones and growth factors [132]. Indeed, metastases from breast cancers to bone involve cross-talk between tumor and bone cells that include tumor-secreted factors that can stimulate bone marrow cell proliferation, resulting in MDSCs that prevent the death of DTCs from tumor-specific cytotoxic T-lymphocytes (CTLs) [133]. Additionally, tumor-associated MDSCs, TAM, neutrophils, and fibroblasts can support the infiltration and expansion of non-transformed cells, including endothelial cells and their precursors, contributing to the vascularization of a micro-metastatic site [134]. Together, these processes support the survival of DTCs and the formation of micro-metastatic foci [28] by inhibiting tumor-antigen specific CTL infiltration via T-regs (T-regulatory cells) and MDSCs [135], thereby supporting their release from dormancy and facilitating the survival and growth of tumor cells.

Accumulating evidence suggests that the tumor microenvironment (TME) provides mechanisms that regulate cell dormancy. For example, hematopoietic stem cells (HSCs) are capable of long-term survival within a state of dormancy [136] and are regulated by interactions with unique tissue microenvironments or “niches” in bone [136]. DTCs from several tumor pathologies have been reported to hijack these endogenous HSC regulatory mechanisms. Thus, the CXCL12/CXCR4 chemokine signaling axis [137] contributes to HSC homing and quiescence [138], and is used by prostate and breast cancer cells during tumor cell arrest and dormancy in bone [139]. Further, tumor cell arrest occurs as part of an interaction with the surrounding microenvironment (niche) initiating a series of adaptive responses involving cell intrinsic signaling programs. This arrest together with niche-specific paracrine signals can induce cellular dormancy associated with chronic tumor cell survival. However, the process of dormant cell reactivation is less understood and appears to be stochastic, whereby a proportion of tumor cells escape from dormancy and initiate growth into a micro-metastatic focus via mechanisms that remain poorly characterized.

Inflammatory processes by which dormant cancer cells can be reactivated and progress into occult metastases are critical to relapse. During sustained inflammation, lung resident neutrophils can produce extracellular traps, which are a mixture of DNA and cytotoxic proteins and proteases. These extracellular traps can initiate the reactivation of dormant cancer cells by remodeling the surrounding extracellular matrix, resulting in growth into micro-metastases [140]. Indeed, integrin and extracellular matrix remodeling events have been described to be part of central dormant cell reactivation mechanisms [141] providing potential therapeutic mechanisms for intervention.

Prostate and luminal breast cancers preferentially metastasize to bones while triple-negative breast cancers have a predilection for visceral organs. Indeed, these niche environments have a series of different functions that regulate tumor cell arrest. The endosteal niche has a role in the arrest of myeloma cells that support the survival and growth of HPCs but may also have a similar function and overlap with DTCs [142]; inhibiting an analysis of the role for the endosteal niche. For example, MM patients whose HSCs were mobilized with G-CSF were found to have an increase in the mobilization of monoclonal plasma cells [143]. CXCL12 has been shown to have a role in the regulation of HSC maintenance, proliferation, localization, trafficking/mobilization, and self-renewal, occurring in bone marrow niches within which dormant DTCs reside. [144] CXCL12 and the αvβ3 integrin aid in binding of DTCs and HSCs to bone matrix proteins, supporting interactions within these niches for prolonged periods [145]. For breast and prostate cancer tumor cells, their preferential interaction with endosteal niches has been associated with CXCR4 expression as well [146, 147], supporting interactions within these niches for prolonged periods. [145] Other studies with acute lymphoblastic leukemia (ALL) cells have shown that extracellular osteopontin, a matrix protein with diverse biological functions, within the endosteal niche supports the induction of dormancy and cell cycle arrest. [148]

BM niches provide a complex microenvironment incorporating many cell types including endothelial cells, adipocytes, osteoclasts, myeloid cells, and cells of osteoblastic lineage [149]. These niches provide homing signals for HSCs in support of their normal function [150]. It has been demonstrated that increasing HSC niches facilitates an increase in the number of BM DTCs [142], suggesting that these homing signals can also facilitate PC metastasis. One mediator of HSC arrest and mobilization is the chemo-attractant, CXCL12 [151]. Recently, it was shown that BM stromal cells with heightened levels of CXCL12 increased the recruitment of PCs into the bone marrow, promoted proliferation of PC cells, and protects PC cells from chemotherapy-induced apoptosis [152], suggesting that DTCs may be home to the HSC niche using similar mechanisms to HSCs themselves. Further, given that cancer cells secrete CSFs [153], which can mobilize HSC as well as DTCs, studies have suggested that both DTCs [142] and HSC mobilizing agents such as G-CSF or CXCR4 inhibitors can mobilize DTCs back into the PB from the BM [154].

As discussed above, primary tumors can modulate the microenvironment of distant organs and metastases but may not have a direct role in tumor cell arrest via the formation of a metastatic niche. Bulky tumors are associated with neutrophilia, as well as circulating and organ-infiltrating MDSCs, due to tumor secretion of growth factors [155, 156]. Consistent with this relationship, the frequency of circulating MDSCs is reduced by surgical debulking or primary tumor resection. [157] However, MDSCs may not have a critical role in the arrest of CTCs and the formation of DTCs, as the arrest of CTCs can occur early in tumor growth and progression prior to the establishment of a primary tumor of sufficient size to result in neutrophilia. While rodent studies have suggested that MDSCs in premetastatic niches may have a role in tumor cell arrest [158, 159], the rapid growth of the primary tumor in animal models may not mimic the timeline that occurs clinically [53, 160]. Further, given the immunosuppressive activity of MDSCs, i.e., downregulation of adaptive immunity, we posit that their role in tumor progression may be associated with the release of DTC from dormancy by suppressing adaptive host immunity that we suggest is critical to the development of overt metastatic foci. This may be related to MDSC infiltration of organ capillary beds following growth of the primary tumor to a size sufficient to secrete growth factors sufficient to expand and mobilize MDSCs. Given that the frequency of circulating MDSCs is directly correlated with tumor burden [161], it is unlikely that a primary tumor early in progression can affect CTC arrest and survival at secondary sites. However, MDSCs may have an important role in sustaining the survival and growth of DTCs and micro-metastatic foci by conferring resistance to host immunosurveillance and immunotherapy. MDSCs may also contribute to the organ specificity of metastasis due to regional support of tumor cell escape from host adoptive immunity [69], as well as establishing of an organ specificity of CTC arrest by the secretion of growth factors that regulate the survival and growth of tumor cells in DTCs and micro-metastatic foci. Thus, while lesion-infiltrating lymphocytes may contribute to tumor cell dormancy, MDSCs may also release DTCs from dormancy in an organ-specific manner, allowing the outgrowth of micro-metastatic foci. The spleen, arguably a rare site for metastasis formation [162], is one example of organ-specific controlled tumor cell growth [163] due in part to it being a relatively hostile environment for tumor cells due to high number of T-cells [164–166]. Thus, T-cells can control tumor cell growth, while metastatic site infiltration by MDSCs, in association with their immunosuppressive activity, may facilitate the survival and growth of DTCs and micro-metastatic foci.

The role of MDSCs in CTC arrest, DTC formation, release of DTCs from dormancy, and tumor progression remains controversial, requiring additional investigation. Sophisticated tumor models and techniques are required to address questions regarding pre-metastatic niche DTC development and maintenance, i.e., dormancy. It is only with such studies that we will be able to identify and develop therapeutic approaches to inhibit neoplastic progression.

Therapeutic regulation of MDSCs in neoplasia

Immunotherapies have been rapidly developing, providing promising therapeutic options for cancers, including patients diagnosed with advanced disease. These novel therapies include immune checkpoint inhibitors (ICIs), cellular immune therapies like adoptive transfer of engineered T-cells, cancer vaccines, and oncolytic virus. However, the immunosuppressive microenvironment mediated or induced by cancers limit the efficacy of these novel immunotherapies. Immunosuppression is associated with innate immune cells such as MDSCs, TAMs, tumor-associated neutrophils (TANs), tumor-associated dendritic cells (DCs), and adoptive immune cells like T-regs that are the main cellular components within the TME. Emerging evidence regarding the role of MDSCs in cancer progression and their association with poor clinical outcomes [166, 167] has stimulated an exploitation of MDSCs as targets for cancer treatment often in combination with other forms of immunotherapy including tumor vaccines. Further, cancer tissues with high MDSC infiltration have been shown to be associated with patient resistance to immunotherapies. [168] Most of the current clinical trials targeting MDSC regulation employ off-label use of Food and Drug Administration (FDA)-approved drugs to assess their efficacy as monotherapeutics or in combination with other immune-modulating therapeutic strategies. Currently, MDSC-targeting modalities include approaches to deplete MDSCs [169], inhibit MDSC-mediated immunosuppressive mechanisms [169], induce MDSC differentiation [89], and block MDSC proliferation and recruitment to tumor sites [169, 170]. Based on this, the development of combined immunotherapies that target MDSC-mediated immunosuppressive pathways to improve the antitumor efficacy of immunotherapy has a broad potential. [171] As part of our discussion focused on clinical approaches to target MDSCs and their bioactivities, we have emphasized clinical studies. The majority of studies on drugs with potential to regulate MDSCs, both off target and novel, have been undertaken using preclinical models; however, we have limited this review largely to therapeutics examined clinically and which have shown provisional activity based on immune surrogates (Table 1).

Table 1.

Therapeutic agents that have demonstrated efficacy against MDSCs or other biomarkers of myeloid-associated immunosuppression in clinical studies

Drug class	Drug	Diseases	Findings
Cytotoxic agents	Capecitabine + bevacizumab (anti-VEGF)	GBM	↓ % Circulating MDSCs,↑ intratumoral infiltration by CTLs, ↓ CTLA-4 and PD-1 expression on macrophages and CTLA-4 on lymphocytes [167]
	Gemcitabine	PDAC	↓ % Circulating G-MDSCs [172]
	Gemcitabine + capecitabine	PDAC	↓ Total circulating MDSCs [175]
	FOLFOX	CRC	↓ total MDSCs [177]
	FOLFOX + bevacizumab	CRC	↓ % Circulating G-MDSCs [176]
	Everolimus + low-dose cyclophosphamide	mRCC	↓ In MDSC, T-regs and DC subsets,↑ CD8 T-cells and DC subsets [325]
	Cabozantinib + nivolumab	mUC	↓ In MDSC, T-regs and DC subsets and decrease in MDSCs was associated with better PFS and OS [326]
	Nivolumab + temozolomide	SCLC	↓ In MDSC and ↑ in T-cell functions [327]
Therapeutic liver-X nuclear receptor (LXR) agonist	RGX-104	Solid tumors	↓MDSC frequency, increased CTL responses [328]
PDE-5 inhibitors	Tadalafil	MM	↓ % M-MDSCs, expression of ARG1, and iNOS in BM, ↓ tyrosine nitrosylation, ↑ % and proliferation of CD8⁺IFN-γ⁺ and TCR-ζ⁺CTLs [191]
		HNSCC	↓ Expression of ARG1 and iNOS, ↓ % circulating MDSCs [189]
		Melanoma	↓ NO production, ↑ T-cell recruitment to tumor sites [193]
	Sildenafil	MM and HNSCC	NCT02466802, restored T-cell proliferation in PBMC [329]
Arginase inhibitors	CB-1158	Lung cancer	↑ T-cell proliferation in patient-derived G-MDSC-conditioned media [202]
Arginase inhibitors	CB-1158	CRC	Demonstrated minimal treatment-related toxicities [203]
iNOS inhibitors	L-NMMA + docetaxel	Triple-negative breast cancer	Decreased arginase levels and an ORR of 45.8% in patients treated with L-NMMA and taxane
	NCX-4016	Healthy volunteers	↓ Monocyte activation, ↓ IL-6 levels, ↓ CD11b expression on monocytes (17.5 mg/kg) [210]
	NCX-4016	CRC (mouse model)	↓ iNOS and ARG1 activity by CD11b monocytes [209]
CSF1R inhibitors	GW-2580	AML	↓ CSF1R^hiHLA-DR⁺CD33⁺ monocytes (unclear whether these are myeloid suppressor cells) [213]
	Pexidartinib + paclitaxel	Advanced solid tumors	Resulted in clinical benefit and ORR 16%, ↓ % circulating CD14dimCD16 + non-classical monocytes [330]
	Pexidartinib	GBM	↓ % Circulating CD14^dimCD16⁺ non-classical monocytes, ↓ expression of intratumoral Iba1 + microglia, however, did not improve patient progression-free survival [220]
	Imatinib	CML	↓ % Circulating G-MDSCs [222]
S100A8/9 inhibition	Tasquinimod	mCRPC	↓ Recruitment of MDSC, decrease monocytes, M1 polarization and prolong PFS [331]
CD33	BI 836,858	MDS	↓ ROS and MDSC [259]
CD33	AMV564	MDS, AML, melanoma	↓ MDSC, increase CTL and reduce tumor burden [262]
Immune checkpoint inhibitors	Ipilimumab (CTLA-4 inhibitor)	Melanoma	Found to result in greater OS in patients with lower MDSC frequency [290]
			↓ NO production by M-MDSCs and ↓ % PD-1 + G-MDSCs were found to be biomarkers of response to therapy [291]
			↓ % Circulating G-MDSCs and ARG1 + myeloid cells [292]
			↓ % G-MDSCs, ↓ iNOS and ARG1 expression [294]
	Pembrolizumab (PD-1 inhibitor)	Urothelial carcinoma	↓ % PD-1⁺ M-MDSCs and iMDSCs [296]
	Pembrolizumab + chemotherapy	NSCLC	Significantly improved OS compared to standard of care alone [321]
	Atezolizumab, avelumab (PD-L1 inhibitors)	Urothelial carcinoma	↓ % PD-L1⁺ M-MDSCs [296]
	Ibrutinib (BTK and ITK inhibitor)	MM	Inhibits BTK phosphorylation on MDSCs generated from patient PBMCs and MDSC migration, generation, and nitrate production in vitro [229]
	Ibrutinib (BTK and ITK inhibitor)	CLL	↑ Absolute number of CD4 + and CD8 + T-cells, ↓ number of circulating G-MDSCs [230]
	Ibrutinib + nivolumab (PD-1 inhibitor)	Metastatic solid tumors	↓ % Circulating MDSCs in the first cycle of therapy, ↑ T-cell function, ↓ plasma chemokines involved in MDSC trafficking (IL-12, CCL2, CCL3, CCL4) [235]
Chemokine inhibitors	HuMax-IL8 (anti-IL-8 monoclonal antibody) (BMS-986253)	Metastatic or unresectable solid tumors	↓ Serum IL-8 but no significant changes in circulating MDSCs [241]
	BL-8040 (CXCR4 inhibitor) + pembrolizumab (PD-1 inhibitor) + chemotherapy	PDAC	↑ Intratumoral CD8 + effector T-cells, ↓ metastasis infiltration by MDSCs, ↑ circulating CD4⁺ and CD8⁺ T-cells, ↓ circulating T-regs, resulted in an overall response rate of 32% [243]
	SX-682 inhibitor of CXCR1/2 signaling	Melanoma, PDAC, mCRC, MDS	NCT03161431, NCT04599140 NCT04245397, and NCT04477343; no results published to date. [247]
	Reparixin (repertaxin) + / − paclitaxel	mBC, TNBC, COVID-19, pancreatic islet auto Tx	NCT02370238, NCT02001974, NCT01861054; no flow results published to date. [332]
	Ulocuplumab (BMS-936564)	Relapsed MM	Safe with acceptable AEs and leads to a high response rate [244]
	AZD5069 + enzalutamide	mProstate CA	NCT03177187 [332]
TK and JAK/STAT inhibition	Sunitinib (multi-kinase inhibitor)	RCC	↓ % PB, MDSCs and induced MDSC apoptosis in vitro, ↓ % circulating MDSCs (which also correlated with ↑ IFN-γ production) [282]
	Sunitinib + stereotactic body radiotherapy	Oligometastatic disease	↓ % Circulating MDSCs [283]
	Ruxolitinib (JAK1/2 inhibitor)	Myeloproliferative neoplasms	↓ % Circulating G-MDSCs, ↓ number of T-regs, ↓ pSTAT5 expression [274]
	Acalabrutinib + pembrolizumab	Advanced pancreatic CA	↓ % Circulating G-MDSCs, with limited clinical activity [333]
COX-2 inhibitor	Celecoxib	Lung CA, colon carcinoma, breast CA, cervix CA, endometrium CA,	NCT00046839, NCT03026140, NCT02429427, NCT00152828, NCT03896113 Celecoxib ↓MDSC‐suppressive function and ARG-1 levels [334]
Anti-cancer vaccines and MDSC inhibition	Nelipepimut-S	Breast cancer	↑ CTL response, ↓ % T-regs [335]
	Personalized cancer peptide vaccine + gemcitabine	PDAC	↓ Tumor size [310]
	INGN-225 (autologous DC vaccine transduced with modified adenoviral p53) + ATRA	SCLC	43.4% of patients developed a tumor-specific T-cell response [336] 52% of patients had p53-specific T-cell response, 61.9% of pts receiving the vaccine achieved complete or partial treatment response, and ↑ IFN-γ production, however, ↑ circulating immature myeloid cells including MDSCs [337]
	p53MVA + gemcitabine	Platinum-resistant ovarian cancer	↑ p53-reactive CD4⁺ and CD8⁺ T-cells but no effect on circulating MDSCs or T-regs [338]
VEGF inhibitors	Bevacizumab	NSCLC	↓ % Circulating G-MDSCs [339]
VEGF inhibitors	Bevacizumab + Robustlyim	EGFR mutant lung AdCA	↓ % Circulating S100A9 + M-MDSCs [340]
Modulation of myeloid cell differentiation	Zoledronic acid	PDAC	No effect on MDSCs, thought to be due to low dose [227]
	ATRA	Metastatic RCC	↓ % Circulating Lin⁻HLA-DR⁻CD33⁺ myeloid cells [265]
	ATRA + ipilimumab (CTLA-4 inhibitor)	Advanced melanoma	↓ % Circulating MDSCs and expression of immunosuppressive markers [267]
	ATRA + atezolizumab	mNSCLC	↓ Recruitment of MDSCs [341]
	Vitamin D3	HNSCC	Inhibited cancer progression and recurrence, ↑ disease-free survival [269]
	Vitamin D3	HNSCC	↓ % Circulating CD34⁺ suppressor cells and serum GM-CSF but they increased again after 6 weeks²⁷¹

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Chemotherapy-associated depletion and inhibition of MDSC proliferation

In addition to tumor cytotoxicity, off-target immune regulation has been documented for some chemotherapeutic agents. However, clinical studies with chemotherapies render it difficult to identify whether the impact of the intervention is due to decrease in MDSCs that is influencing clinical outcomes or whether the reduction in MDSC number and function is due to another therapy or reduced tumor burden secondary to the chemotherapy. In preclinical studies, these activities can be assessed by testing individual therapies versus in combination, an approach not ethically appropriate clinically. Such studies with chemotherapeutics include capecitabine, a 5-fluorouracil (5-FU) prodrug that can significantly decrease the frequency of circulating MDSCs and increase CTL infiltration, as reported with glioblastoma multiforme (GBM) tumors, theoretically enhancing antitumor activity [167]. Similarly, the antimetabolite gemcitabine has been reported to significantly decrease the frequency of circulating G-MDSCs, but not M-MDSCs, in studies recruiting patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) [172]. However, in this study, the authors examined MDSC frequency using cryopreserved PB mononuclear cells (PBMC), which is a concern as MDSCs are sensitive to freeze–thaw lysis [173, 174]. In a separate study, PDAC patients were administered gemcitabine with capecitabine (GemCap) and documented a decrease in the frequency of circulating MDSCs in 8 out of 19 patients [175]. In another arm of this study, 21 patients were treated with GemCap, in addition to an anti-cancer vaccine, and granulocyte–macrophage (GM)-CSF to reduce chemotherapy-associated myelosuppression, demonstrating a decreased frequency of circulating MDSCs suggested to be associated with the GemCap chemotherapy. [175] The decrease in the frequency of MDSCs in both cohorts was associated with reduced serum levels of cytokines and inversely correlated with changes in tumor size [175]. However, this study again examined MDSC frequencies using cryopreserved peripheral blood mononuclear cells (PBMCs) [175], limiting conclusions into cytotoxic agent reduction in the frequency of MDSCs.

In patients with metastatic CRC treated with FOLFOX (folic acid, 5-FU, and oxaliplatin) in combination with bevacizumab, a significant decrease in the frequency of circulating G-MDSCs, but not M-MDSCs [176], and improved progression-free survival (PFS) [176] was observed. However, some chemotherapeutic protocols have been suggested to increase MDSC frequency, negatively affecting the tumor microenvironment. This difference in response to cytotoxic drugs was found in a study on 23 metastatic CRC patients treated with either FOLFOX or FOLFIRI (folic acid, 5-FU, and irinotecan) chemotherapeutic regimens. FOLFOX-treated patients demonstrated a decrease in the frequency of MDSCs, whereas an increased frequency of MDSCs was observed in the FOLFIRI-treated group [177]. The increased frequency of MDSCs and chemotherapy regulation was also documented in a clinical study on breast cancer patients given 4 cycles of doxorubicin plus cyclophosphamide (AC) every 2 weeks followed by 4 cycles of dose-dense paclitaxel [59]. In addition, during all of the cycles of chemotherapy, peg-filgrastim (PEGylated G-CSF) was administered on day 2 to reduce therapy-induced neutropenia [178]. This is critical as following several cycles of chemotherapy, patients become myelosuppressed, placing them at increased risk of potentially life treating microbial infections, such that administration of myelopoietic growth factors enables continuation of chemotherapy without interruption and dose de-escalation [179]. The two phases of the AC and paclitaxel protocol resulted in a different outcome in each phase based on the frequency and absolute number of circulating MDSCs versus baseline numbers [59]. AC administration resulted in significantly increased frequency and absolute number of circulating MDSCs (11.72 and 1157 cells/μL) as compared to paclitaxel (3.65 and 257 cells/μL) [59]. The increased MDSC frequency was suggested to be due to the use of peg-filgrastim and repeated cycles of chemotherapy [59]. The response to peg-filgrastim is consistent with prior studies demonstrating an increase in MDSC frequency following growth factor administration [180], as have repeated cycles of chemotherapy that may be positively associated with increased suppressor cell activity [92]. Despite the demonstrated association of these various chemotherapeutic agents with MDSC dynamics, it has been difficult to correlate changes in MDSC frequency with clinical efficacy supporting a potential for a poly-therapeutic approach in the regulation of MDSCs.

In patients diagnosed with mesothelioma, a recent study examined the impact of gemcitabine treatment on the frequency of MDSCs and lymphocytes, and progression free survival (PFS). The frequency of MDSCs and lymphocytes was assessed at baseline and 3 weeks following start of gemcitabine therapy as compared to patients receiving best supportive care (BSC) as part of the NVALT19-trial. [181] Gemcitabine treatment was significantly associated with increased NK and decreased T-reg cell proliferation in the experimental group as compared to the BSC cohort. Further, the frequency of MDSCs was lower in gemcitabine-treated patients and correlated with an increase in T-cell proliferation following treatment. The preliminary analysis suggested that the increase in NK-cell proliferation and PD-1 expression on T cells following gemcitabine therapy was associated with improved PFS and OS. The observations from these studies suggest preferential activation of anti-tumor immune cell populations and inhibition of T-regs and MDSCs by gemcitabine administration.

Attenuation of MDSC function

As mentioned above, ARG1 decreases extracellular L-arginine levels, which is required for T-cell function. [182] For ARG1 to function, tumor-derived prostaglandin E2 (PGE2), produced by cyclooxygenase-2 (COX2), has an important role. [183] In addition, ROS production by MDSCs is promoted by COX-2 and PGE2 activities. [183, 184] It has been shown in autochthonous tumor models that blockade of PGE2 synthesis by the administration of the COX2 inhibitor celecoxib results in the downregulation of ARG1 expression and ROS production by MDSCs, followed by improved antitumor T-cell function [185] and cancer chemoprevention. [186] Clinically, due in part to toxicity concerns (GI and cardiac), COX-2 inhibitors have not been aggressively studied for chemoprevention and cancer therapy [187]. Recently an adjuvant trial of celecoxib for patients with metastatic CRC was reported [188]. In this small randomized study, 54 patients with metastatic CRC were randomized into 2 groups: a control group that received 6 cycles of the FOLFIRI regimen as compared to a FOLFIRI and celecoxib group (receiving 6 cycles of FOLFIRI plus 200 mg twice daily of celecoxib over 3 months). Patients were assessed at baseline and at the end of intervention using RECIST criteria (Response Evaluation Criteria in Solid Tumors) and an evaluation of serum VEGF, soluble FAS (sFAS), sFAS ligand (sFAS-L), and epithelial neutrophil-activating peptide -78 (ENA-78/CXCL5) levels. Three months following initiation of therapy, the celecoxib/FOLFIRI cohort had a significantly better ORR, significantly lower serum levels of VEGF, CXCL5, and sFASL, and significantly higher sFAS serum levels. Further, the clinical outcomes of patients in the celecoxib/FOLFIRI cohort, i.e., PFS and 1-year OS, were significantly improved relative to the FOLFIRI cohort.

Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil promote the accumulation of intracellular cyclic guanosine monophosphate (cGMP) and can trigger downstream effects that inhibit MDSC function [189, 190]. In early studies with PDE5 inhibitors, a patient with refractory multiple myeloma (MM) was treated with tadalafil and found to have reduced serum monoclonal immunoglobulin (M-protein) levels [191]. Later studies on MM patients [191] demonstrated that the addition of tadalafil to concurrent treatment regimens significantly reduced the frequency of BM M-MDSCs (HLA-DR⁻CD14⁺) at 6 months, but following 6–11 months of treatment, BM M-MDSC frequency was observed to be increased. However, a significant decrease in iNOS and ARG1 levels was observed [191]. Concomitant with the decrease in intracellular iNOS and ARG1 expression by M-MDSCs in the BM, a significant decrease in tyrosine nitrosylation was observed at 11 + months post-treatment [191] in association with an increase in the frequency and proliferation of stimulated BM CD8⁺IFNγ⁺ (interferon) and TCR-ζ⁺CTL [191]. This is expected as iNOS, ROS, and ARG1 promote MDSC-mediated T-cell suppression by contributing to the nitrosylation of the T-cell receptor [87, 88], depletion of L-arginine, downregulation of TCR- ζ chain expression [192], and upregulation of toxic mediators including activated O₂ radicals and NO [75–77]. Thus, tadalafil administration and the associated decrease in iNOS and ARG1 expression have been suggested to result in increased CD8⁺ T-cell activity by decreased MDSC function and number in MM patients [191].

The regulation of MDSCs by PDE-5 inhibition has been reported for other cancers including metastatic melanoma patients with stable disease (SD). In these studies, tadalafil treatment did not significantly reduce the frequency of circulating M-MDSCs; however, it did reduce NO production by M-MDSCs in metastatic lesions in 2 out of 3 patients who had SD, which was associated with significant increase in tumor infiltrating CD8 T-cells [193]. In head and neck squamous cell carcinoma (HNSCC) patients, PDE-5 inhibition was shown to significantly decrease the frequency and intracellular levels of ARG1 and iNOS in circulating MDSCs compared to baseline levels [189]. Further, T-cell proliferation and activation were significantly increased in tadalafil-treated HNSCC patients [189]. These studies suggested that PDE-5 inhibitors can mitigate T-cell inhibition and potentially improve tumor-specific CTL responses by reducing MDSC frequency and inhibiting iNOS and ARG1 levels [189, 194].

In a recent retrospective cohort analysis of 3100 patients with prostate cancer treated with radical prostatectomy between 2003 and 2015, patients were subset into those receiving a PDE-5 inhibitor or non-recipients (controls) [195]. Biochemical RFS and OS at 5 and 10 years were reported. The biochemical RFS for control patients at 5 and 10 years was 87.6 and 85.3%, respectively, and the OS at these times was 97.9 and 94.5%. In the cohort that received PDE-5 inhibitors, the RFS and OS significantly increased with a RFS of was 94.3 and 93.2% at 5- and 10-year follow-up, respectively, and OS was 99.2 and 95.8% at these time points. A multivariate analysis was also undertaken documenting that PDE-5 inhibitor administration was associated with lower risk of biochemical recurrence and death when corrected for other variables.

ARG1 expression is frequently increased in myeloid cells of cancer patients, including breast cancer [196, 197] and CRC [198]; however, it is unclear if a decrease in ARG1 expression can contribute to patient survival [199]. In one study that examined critically ill patients, the frequency of G-MDSCs was negatively correlated with L-arginine plasma concentration. Further, in this study, patient mortality was directly associated with frequency of G-MDSCs (CD15⁺CD14⁻HLA-DR⁻ and Lin⁻CD33⁺HLA-DR⁻) on day 1 of hospital admission [200]. Based on these and similar observations, it has been suggested that L-arginine depletion by G-MDSCs may contribute to increased risk of patient mortality and higher frequency of G-MDSCs. A number of investigational new drugs targeting ARG1 are under investigation using preclinical models and are currently in clinical trials. One such agent studied in a phase I/II clinical study in combination with gemcitabine for advanced biliary cancers (INCB001158) was reported to result in a median PFS of 8.5 months. [201] A second arginase inhibitor, CB-1158, has been shown to increase T-cell proliferation in medium conditioned by G-MDSCs that were isolated from lung cancer patients [202] and clinically has shown minimal toxicities and efficiencies in a cohort of solid tumor patients in an ongoing clinical trial [203, 204] (NCT02903914).

Investigational iNOS inhibitors such as N(G)-monomethyl L-arginine (L-NMMA) have been shown to decrease MDSC suppressive activity in murine tumor models [205] and are currently being investigated in several clinical cancer trials (NCT04095689, NCT02834403, and NCT03236935). In a recent report of a phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemo-refractory, locally advanced breast cancer (LABC), or metastatic triple negative breast cancer (TNBC) (NCT02834403) immune cell correlates of response were examined. [206] In this study on 35 patients, the ORR was 45.8%. Phenotypic studies using mass cytometry time of flight (CyTOF) analysis of PB immune cells at the end of therapy revealed that chemotherapy non-responders had increased expression of markers associated with M2 macrophage polarization and increased concentrations of circulating interleukin (IL)-6 and IL-10. In contrast, chemotherapy responders had increased frequency of CD15⁺ neutrophils with decreased arginase levels. The investigators concluded that L-NMMA combined with taxane therapy warrants additional investigation in larger clinical studies of breast cancer patients.

In similar studies, NCX-4016, an NO-releasing aspirin derivative, was reported to increase, rather than decrease, plasma NO levels by nearly twofold [207], thereby inhibiting iNOS expression [208]. NCX-4016 was observed to inhibit iNOS and ARG1 activity by CD11b⁺ cells [209], resulting in increased anti-tumor immune activity [209], elevated numbers of CD8⁺ T-cells [209], and increased IFN-γ secretion [209]. In studies on NCX-4016 administration to healthy volunteers, it was found to inhibit monocyte activation, lower IL-6 levels, and reduce CD11b expression on monocytes, suggesting that it can inhibit MDSC-mediated immunosuppressive activity in humans [210]. Despite the evidence regarding iNOS inhibition, preclinical studies have indicated that NO and peroxynitrites produced by macrophages can result in cytotoxicity to tumor cells [205], potentially overcoming the effects of iNOS- and NO-induced inhibition of CTL activity [85, 86]. Therefore, it remains unclear whether iNOS inhibition or NO supplementation may be worthwhile in the treatment of cancer given the diverse bioactivities of NO despite their potential to curb tumor immune evasion.

Inhibition of myeloid cell growth factors has been shown to reduce MDSC proliferation, as well as tumor infiltration by MDSCs and TAMs [211]. We note that studies on circulating and tissue-infiltrating myeloid cells are controversial, as the phenotypes of infiltrating TANs, TAMs, and MDSCs are not clearly differentiated. Thus, in our discussion, we use the nomenclature from each referenced manuscript, with the understanding that the cellular phenotype and function may be independent of terminology used. The most extensively studied biologics have targeted colony stimulating factor-1 receptors (CSF1R), also known as c-fms proto-oncogene and CD115. Several CSF1R inhibitors are currently in clinical trials, providing some encouraging results [212]. Additionally, their administration has been reported to decrease monocytes and MDSCs and, in some studies, to be positively associated with patient outcomes. In AML patients, the CSF1R inhibitor GW-2580 has been reported to decrease monocyte frequency including the frequency of HLA-DR + CD33 + CSF1R^hi monocytes [213]. Conversely, CSF1R^hi monocytes that co-expressed CD16 and CD66b were reported to be less responsive to GW-2580 intervention. While all MDSCs are HLA-DR^low/− and express CD33, some reports have further differentiated their phenotypes based on the expression of CD16⁻ [214]. Thus, it is unknown whether the CSF1R^hi monocyte subsets from this study included all MDSCs. However, in vitro studies with blood samples from chronic lymphocytic leukemia (CLL) patients revealed that GW-2580 co-culture decreased the total number of nurse-like cells (NLCs), a monocyte subset in CLL patients that interacts with TAMs and are associated with tumor progression in CLL patients [215, 216].

The small molecular weight CSF1R inhibitor pexidartinib (formerly PLX-3397), which is an inhibitor of tyrosine kinases (TK) involved in hematopoiesis [217] including not only CSF1R but also c-KIT (stem cell factor receptor), Flt-3 (Fms-related tyrosine kinase 3), and VEGFR, has been studied in patients with advanced solid tumors. The administration of pexidartinib in combination with paclitaxel has shown clinical benefit (CR, P, and SD) in 19 of 38 patients including CRs in 16% of the patients studied [218]. Furthermore, the administration of pexidartinib was associated with a 57–100% decrease in the frequency of circulating CD14^dimCD16⁺ (non-classical) monocytes, suggesting a relationship between clinical benefit and CSF1R inhibition, as nonclassical monocytes have high expression levels of CSF1R as compared to other monocyte subsets [218, 219]. Similarly, pexidartinib administration to GBM patients was found to reduce the frequency of circulating CD14^dimCD16⁺ monocytes by nearly 50% and to significantly decrease intratumoral Iba1⁺ microglia cells, a resident macrophage of neural tissue and a form of TAM in neurologic malignancies [220]. Unfortunately, pexidartinib has not been reported to improve PFS in this subset of GBM patients [220]. Another TKI, imatinib, with an inhibitory profile of activity similar to pexidartinib is currently used in the treatment of BCR-ABL⁺ chronic myeloid leukemia (CML) and targets CSF1R [221]. Imatinib has been shown to significantly reduce the frequency of circulating G-MDSCs (CD11b⁺CD33⁺CD14⁻HLA‐DR⁻) [222] in patients with CML.

Zoledronic acid (ZA), a bisphosphonate derivative, is used clinically to inhibit bone-resorbing osteoclasts, which are residential bone macrophages derived from myeloid progenitors, for treatment of osteopenia [223] and to prolong disease-free survival (DFS) in post-menopausal breast cancer patients [224]. Studies on tumor models using ZA have demonstrated a decrease in circulating MDSCs and increased T-cell infiltration into tumors [225, 226]. To date, one clinical study on 15 PDAC patients with non-metastatic disease reported the regulation of MDSCs by ZA [227]. This was observed in patients that received ZA 2 weeks prior to surgery and twice, 4 weeks apart, following surgery [227]. In this study, flow analysis was undertaken on PB samples obtained prior to ZA injection and 3 months after surgery processed by Ficoll-density centrifugation and cryopreservation [227]. Perhaps due to density gradient separation and freezing, no difference was observed in the frequency of G-MDSCs in the PB or BM following ZA treatment [227]. Further, the authors suggested that the lack of MDSC response to ZA administration might have been due to insufficient dose or duration of ZA administration [227]. However, as mentioned previously, MDSCs and granulocytes are sensitive to freeze/thaw lysis [173, 174]; potentially obscuring their assessment.

Inhibition of MDSC recruitment

Ibrutinib, a Bruton’s tyrosine kinase (BTK) and interleukin-2 (IL-2)-inducible kinase (ITK) inhibitor, has been shown to have off-target effects on MDSC mobilization, resulting in studies as an immunomodulatory therapy against solid tumors [228]. Human and murine MDSCs express BTK [229], and treatment with ibrutinib can inhibit the phosphorylation of BTK in MDSCs based on in vitro studies with PB from metastatic melanoma patients [229]. In vitro studies using PB samples have revealed that ibrutinib administration inhibits MDSC migration, generation, and nitrate production [229]. In a clinical study on CLL patients who were administered ibrutiniban, increase in the absolute numbers of CD4⁺ and CD8⁺ T-cells and decrease in circulating G-MDSCs were observed [230]. Despite the rationale for the bioactivity of ibrutinib, current clinical studies have not documented any survival benefit either alone or in combination with other therapies for patients with pancreatic [231], breast [232, 233], or neuroendocrine cancers [234]. However, preliminary results from an ongoing study in patients with solid tumors that were treated with ibrutinib observed a decrease in plasma levels of chemokines involved in MDSC trafficking [235] that have stimulated similar clinical studies [232, 236]. Thus, an indirect anti-tumor mechanism may be part of on-target inhibition of BTK by ibrutinib and another BTK inhibitor called acalabrutinib through the regulation of cytokines, chemokines, and growth factors. Further, the inhibition of BTK with ibrutinib or acalabrutinib has been shown to impair toll-like receptor (TLR) signaling and inflammasome activation in TAMs, MDSCs, DCs, and B cells, suppressing the secretion of cytokines, chemokines, and growth factors including IL-1b, IL-6, CXCL12, CXCL13, CCL19, and VEGF. Thus, ibrutinib and acalabrutinib appear to have potential clinical benefit to reduce inflammation-associated cancer progression and angiogenesis in the TME. [237]

Antigen-presenting and tumor cells secrete chemokines that recruit inflammatory cells, as well as myeloid progenitors and MDSCs, into the TME. The inhibition of chemokine functions [238] has been shown to block MDSC recruitment [239] and their regulation of tumor progression. One such inhibitor, HuMax-IL8 (also identified as BMS-986253), is a monoclonal antibody that binds IL-8, a chemotactic factor associated with cancer progression and MDSC recruitment to tumor sites [240]. In a dose escalation study on patients with metastatic or unresectable solid tumors, HuMax-IL8 was found to decrease serum IL-8 levels, resulting in significant reduction in IL-8 on day 3 as compared to baseline levels. In addition, SD was observed in 73% of patients with a median treatment duration of 24 weeks [241]. In preclinical studies, HuMax-IL8 has been shown to significantly inhibit MDSC recruitment and to improve CTL activity when given in combination with docetaxel [242]. However, in another clinical study using a mixture of solid tumor patients (N = 3), no significant differences were observed in the frequency of circulating MDSCs and during dose escalation (N = 6) in the dose expansion phase [241]. In contrast to these studies, a combination therapy with a CXCR4 antagonist (BL-8040), a PD-1 inhibitor (pembrolizumab), and chemotherapy in a larger cohort of patients with metastatic PDAC demonstrated an elevated frequency of tumor-infiltrating CD8⁺ effector T-cells and a reduced infiltration by MDSCs in biopsies from tumor metastases [243]. Additionally, a significant increase in circulating CD4⁺ and CD8⁺ T-cells and a significant decrease in T-regs were observed. In the patient cohort that received BL-8040 and pembrolizumab, a disease control rate (DCR) of 34.5% was observed, while in the cohort given BL-8040, pembrolizumab, and chemotherapy, a DCR of 77% and an ORR of 32% were observed. Studies using the CXCR4 antibody ulocuplumab (BMS-936564) in combination with lenalidomide or bortezomib plus dexamethasone for the treatment of MM was examined. In this study, an ORR of 55.2% and a DCR of 72.4% were observed in patients receiving combined therapy [244]. Taken together, these results suggest that there may be a potential benefit for combination chemokine and checkpoint inhibitor therapy to mitigate MDSC recruitment and immunosuppression of tumors.

Other studies have used inhibitors for chemokine ligands for CXCR2, like CXCL2 or CXCL5, which are essential for PMN-MDSC recruitment. Targeting the chemokine receptor CXCR2 can reduce MDSC populations, promote T-cell infiltration, and improve the efficacy of PD-1 blockade in preclinical studies [245, 246]. SX-682, a CXCR1/2 inhibitor, enhanced the T-cell-based immunotherapeutic efficacy in studies using murine tumor models that assessed MDSC-infiltration [247, 248]. The CXCR1/2 inhibitor reparixin showed promise in a window-of-opportunity clinical trial for HER-2-negative breast cancer. Reparaxin was safe, well tolerated, and caused reduction in cancer stem cells in patient tumors [249]. Further, a phase 1b trial in patients with metastatic breast cancer found reparixin to be safe in combination with paclitaxel [250]. Due to the above studies, reparixin was investigated in combination with paclitaxel as a frontline treatment for metastatic TNBC in a phase 2 trial; however, the primary endpoint of prolonged PFS was not met [251]. While there are no CXCR2-targeted drugs currently approved for use in cancer treatment, additional CXCR2 antagonists are also in various stages of clinical development for both neoplastic and inflammatory diseases [252].

S100A8 (calgranulin A, also called myeloid-related protein 8, MRP8) and S100A9 (calgranulin B or myeloid-related protein 14, MRP14) are small molecular calcium-binding proteins with crucial roles in cancer development that can act as diagnostic markers and targets for cancer therapy. [253] MDSCs express both S100A8 and A9 and the corresponding receptors RAGE, acting as a positive feedback loop to chemo-attract MDSCs and increase their immunosuppressive function. [254] Tasquinimod, an oral drug that can bind to S100A9 and inhibits interaction between S100A9 and its sensors, including RAGE and TLR4 [255], has been studied in numerous clinical trials documenting that its administration to cancer patients can decrease blood monocytes, reduce MDSC infiltration of tumors, and polarize TAMs to M1 cells. [256] In a phase II trial, tasquinimod administration was reported to improve the PFS in patients with metastatic castration-resistant prostate cancer (mCRPC) by reducing the recruitment of MDSCs and inhibiting metastasis [257]. In a recent phase III clinical trial (NCT01234311), tasquinimod treatment of mCRPC patients resulted in improved radiologic PFS compared with the placebo group but had no impact on OS. [258]

One marker of G-MDSCs is the expression of CD33 where it has an important role in MDSC-mediated hematopoietic suppressive function following its activation by S100A9. Studies using a fully human, Fc-engineered monoclonal antibody against CD33 (BI 836,858) that suppresses CD33-mediated signal transduction have been shown to improve the bone marrow microenvironment in patients with MDS. [259] In this study, BI 836,858 was shown to reduce MDSC by antibody-dependent cellular cytotoxicity (ADCC), which correlated with increases in granule mobilization and cell death. BI 836,858 has shown to block CD33 downstream signaling, preventing immune-suppressive cytokine secretion, correlating with a significant increase in the formation of progenitor cells colonies. The activation of the CD33 pathway can also cause reactive oxygen species (ROS)-induced genomic instability. Unconjugated, monospecific anti-CD33 antibodies have had disappointing results clinically, showing only modest activity [260]. In contrast to monospecific antibodies, T cell engagers that bind to CD3 and CD33 have shown activity in reducing CD33 + malignant clones in AML patients and activation of T cells. [261] One such bispecific T cell engager, AMV564, is in early-stage clinical trials in patients with advanced solid tumor malignancies, AML, or MDSs (NCT03144245, NCT03516591, and NCT04128423). In these clinical studies, in vitro AMV564 has been shown to decrease MDSCs, increase CTLs, and reduce tumor burden. [262]

Induction of MDSC differentiation

The vitamin A metabolite all-trans retinoic acid (ATRA) is used clinically to induce differentiation of leukemic blasts into mature myeloid cells in patients with acute promyelocytic leukemia [263] and to induce the differentiation of MDSC into macrophages and/or dendritic cells in vitro. In addition, treatment of tumor-bearing mice with ATRA has been shown to result in significant reduction of MDSC in vivo [264]. ATRA specifically targets immature myeloid cells, including MDSCs, by inducing their differentiation through the upregulation of glutathione synthase and glutathione production [265, 266]. Thus, in addition to reducing MDSCs, especially G–MDSCs, the differentiation of M-MDSCs into DCs has additional potential clinical benefit. In one study, administration of ATRA significantly reduced the frequency of Lin⁻HLA-DR⁻CD33⁺ myeloid cells in the PB of mRCC patients 7 and 14 days post-treatment [265]. In another study on advanced-stage melanoma patients, the administration of ATRA with ipilimumab significantly reduced the frequency of circulating MDSCs and their expression of immunosuppressive genes [267]. Similar to ATRA, vitamin D3 has been shown to have anti-inflammatory and immunomodulatory activities [268]. Furthermore, vitamin D3 has been shown to inhibit cancer progression and recurrence and to improve DFS [269]. In a recent murine study, it was shown that MDSCs, especially M-MDSCs, express the vitamin D receptor (VDR) and that following ligation had reduced immunosuppressive activity [270]. In a clinical study on HNSCC patients given escalating doses of vitamin D3, a significant decrease in the frequency of CD34⁺suppressor cells, likely MDSCs, was reported in higher dose groups, in association with significant decrease in serum GM-CSF levels [271]. However, the frequency of CD34⁺ suppressor cells and serum cytokine levels was observed to increase following 6 weeks of treatment [271]. The initial reduction followed by the increase in the frequency of circulating suppressor cells may be due to the lower serum GM-CSF levels in the beginning of the study as compared to week 6 [271]. Based on these early studies, additional clinical research is needed to determine which cancers and associated treatment regimens, as well as patient characteristics, would benefit most from vitamin D3 supplementation.

Tyrosine kinase and JAK inhibitors

The janus kinase (JAK)/STAT, BTK, and mitogen-activated protein kinase (MAPK)-interacting serine/threonine protein kinases 1 and 2 (MNK1/2) pathways have been shown to contribute to the adaptive and innate immune responses that contribute to primary autoimmune disorders and immune response (ir) AEs and myeloplasia [272]. Further, JAK/STAT signaling pathways engage various TKs and downstream effectors involved in MDSC recruitment, expansion, angiogenesis [273], as well as, suppression of T-cell function by interactions with tumor-derived signaling molecules including VEGF, G-CSF, and GM-CSF. Ruxolitinib (Rux), a JAK1/2 inhibitor, has been shown to significantly decrease circulating G-MDSCs and T-regs [274] and the levels of pSTAT5 in patients with myeloproliferative diseases [274]. However, treatment-induced STAT5 activation and an associated reduction in T-cell numbers and pro-inflammatory cytokines could potentially contribute to loss of T-cell function [274]. However, Rux treatment has not been documented to provide clinical benefit for solid tumor patients, including early clinical trials of non-small cell lung cancer (NSCLC) [275] and metastatic pancreatic cancer; [276] although it has received regulatory approval for the treatment of myelofibrosis [277]. Indeed, studies using murine tumors and clinical activity for myelofibrosis suggest that JAK/STAT pathway inhibition has a promise as an MDSC-targeting strategy [278].

Sunitinib, a TKI, has been reported to inhibit the VEGFR-1/2/3, PDGFR-α/β, c-Kit, and FLT-3 and ret proto-oncogene (RET) receptors [279]; most of which support MDSC proliferation [280] and are a frontline therapy for renal carcinoma (RCC) [281]. In a study on RCC patients, a significant decrease in MDSC frequency was observed when patients’ myeloid cells were cultured in vitro with varying concentrations of sunitinib for 48 h, with MDSC apoptosis induced in a dose-dependent manner [282]. Furthermore, in a clinical trial, a subset of patients treated with two cycles of sunitinib were found to have decreased frequencies of MDSCs relative to baseline, a difference that significantly correlated with increase in IFN-γ production [282].I n a separate study, cancer patients with oligometastatic disease were treated with sunitinib prior to stereotactic body radiotherapy [283], and 7 days following sunitinib therapy, patients had a significantly lower frequency of circulating MDSCs (CD33⁺HLA-DR^−/lo). The authors of this study concluded that sunitinib increased the efficacy of SBRT in patients with oligometastases by reversing MDSC and T-reg-mediated immune suppression [283]. Of note, in these studies, M-MDSCs were defined as CD33⁺CD14⁺CD16⁺, differing from most studies, which include HLA-DR^low/− and/or CD11b⁺ cells in the M-MDSC phenotype.

Overview of combining MDSC inhibition with immunotherapy

Immunotherapy has provided another novel approach for cancer treatment with numerous immunotherapies being approved by the FDA for routine use or for investigation. By enhancing T-cell-mediated cytotoxicity, drugs and biologics that restore immune response have shown a therapeutic effect on several cancers. [284, 285] Tumor cytotoxic activity is induced by an antigen-specific signal by T-cell receptor recognition [286] or an antigen-independent signal regulated by co-signaling receptors, for which PD-1 and CTLA-4 are crucial co-inhibitors. [287] Immune checkpoint inhibitors (ICIs) provide a type of immunotherapy that blocks immune checkpoint proteins on tumor cells, including but not limited to programmed death-ligand 1 (PD-L1) and CTL-associated protein 4 (CTLA-4), from binding to their ligands, PD-1 and CD80/86, respectively. These checkpoints limit robust immune responses contributing to tumor evasion by CD8⁺ T-cell immunosurveillance [288]. The CTLA-4 inhibitor ipilimumab, which was approved by the FDA for metastatic melanoma [289], has been shown to improve OS in patients with lower frequencies of MDSCs [290, 291]. Furthermore, ipilimumab has been shown to reduce the frequency of M-MDSCs, their production of NO, and the frequency of PD-1⁺ G-MDSCs [291]. In a study on melanoma patients treated with ipilimumab over 9 weeks, it was demonstrated that a significant reduction in the PB frequency of G-MDSCs and ARG1⁺ myeloid cells was induced as compared to baseline levels [292, 293]. Further, treatment with ipilimumab was found to significantly decrease iNOS and ARG1 expression relative to baseline [294].

A low frequency of MDSCs has also been shown to provide a predictive response marker for melanoma patient and a benefit from ipilimumab treatment [295]. Results from one study suggested that the frequency of M-MDSC provided a predictive response marker, as low frequencies identified patients benefitting from ipilimumab intervention. Interestingly, patients treated with multiple doses of the PD-L1 inhibitors atezolizumab or avelumab have been shown to have a significantly decreased frequency of PB PD-L1⁺M-MDSCs [296]; while multiple doses of the PD-1 inhibitor pembrolizumab have been shown to significantly decrease the frequency of PD-1⁺ M- and i-MDSCs in the PB [2, 96]. Consistent with these observations, several studies have documented a relationship between MDSC infiltration and PD1 blockade resistance, and that selective depletion of MDSCs could restore anti-PD1 therapy efficacy [297, 298]. Studies such as these have suggested that administration of ICIs may be effective in reducing the frequency of MDSCs, cells that express ICI-targeted checkpoint markers, as well as a possible use of MDSCs as biomarkers to predict and/or monitor patient outcomes.

Similar to CTLA-4, the interaction of PD-1 and its ligand, PD-L1, is involved in another important immune inhibitory process, which leads to T effector cell exhaustion and their conversion into T-regs [299]. Clinical trials have documented that blockade of PD-1/PD-L1 signaling can enhance anti-tumor immunoactivity of T cells and clinical outcomes resulting in FDA approval of several biologics. Further, combination therapy with ipilimumab and nivolumab (PD-1 inhibitor) demonstrated additive therapeutic activity against melanoma, advanced UC, mesothelioma, CRC, hepatocellular carcinoma, and NSCLC. [300] Recently, a biologic against LAG-3 has received FDA approval for the treatment of advanced melanoma [301]. This immune checkpoint inhibition can also increase responses to other forms of immunotherapy via monoclonal antibodies targeting tumor-associated antigens, cancer vaccines, adoptive immune cells therapies, and unspecific boosting of the immune system with ILs, IFNs, or TLR-ligands. However, the anticancer effects of all these treatments can be limited by MDSCs through dampening the host’s immune responses against tumors. Consequently, alternative strategies targeting MDSCs combined with active or passive immunotherapies are under extensive study in clinical trials. [302]

The objective of cancer vaccines is to sensitize and activate antigen-specific T-cell responses to kill tumor cells. Despite decades of study, only one vaccine, sipuleucel-T (Provenge®), has received FDA approval, though it has been found to only extend the OS of metastatic prostate cancer patients by 4 months [303]. An investigational vaccine, nelipepimut-S (NeuVax™), for breast cancer that uses GM-CSF as an adjuvant [304, 305] was examined in a phase I/II trial and showed increased CTL responses and decrease in the frequency of T-regs following immunization and indicated favorable responses in patients; however, circulating MDSCs were not assessed [306]. A subsequent phase III trial of NeuVax™ was recently reported and showed that NeuVax alone had no significant clinical effect on breast cancer patients [305]. The use of GM-CSF as an adjuvant increases tumor antigen presentation and, thus, potential anti-tumor responses [304]; however, it also expands MDSCs at higher doses [304, 307]. This provides one of the challenges in maximizing antigen presentation using GM-CSF while minimizing MDSC expansion. In a study on relapsed prostate cancer patients given daily high doses of GM-CSF as a vaccine adjuvant, the patients experienced an increase in the absolute number of MDSCs and T-regs, whereas patients given lower, intermittent doses had fewer MDSCs and T-regs [308]. Additionally, tumor-secreted GM-CSF in mesothelioma patients has been shown to bolster the immunosuppressive activities of G-MDSCs (CD15⁺CD33⁻HLA-DR^low/−CD11b⁺CD66b⁺CD16⁺) granulocytic cells [309]. Similar activities have been observed with G-CSF as discussed in the section of this review titled Chemotherapy-associated depletion and inhibition of MDSC proliferation.

Aside from challenges associated with selecting an appropriate adjuvant to maximize antigen presentation and anti-tumor immunity, chemotherapeutics, as with ICIs, may also minimize the negative impact of inhibitory immune factors and cell populations such as MDSCs on vaccine efficacy. In a clinical trial, patients with advanced pancreatic cancer were given personalized cancer peptide vaccines plus gemcitabine. In this study, 11 of the 13 patients showed clinical responses defined as reduction in tumor size [310]. In a similar study on small cell lung cancer (SCLC) patients, co-administration of INGN-225 (a vaccine comprised of autologous dendritic cells transduced with a modified p53 adenovirus) and ATRA resulted in the development of a tumor-specific T-cell response in 43.3% of patients versus 20% of patients treated with the vaccine alone [311]. In another SCLC trial in which patients also received chemotherapy, the administration of INGN-225 resulted in significant p53-specific T-cell response in 52% of patients, along with persistently elevated IFN-γ production 2–3 weeks after the last vaccine cycle; however, a significant elevation in immature myeloid cells (Lin⁻HLA-DR⁻CD33⁺) was also observed, which included MDSCs [312]. Of the patients who received second-line chemotherapy following vaccine administration, 61.9% achieved a complete or partial response to therapy [312]. In another study, patients with platinum-resistant ovarian cancer were given a non-dendritic cell p53 vaccine (p53MVA; day 15) with gemcitabine (days 1 and 8) over 3 cycles of chemotherapy. Approximately half of the patients had p53-reactive CD4⁺ and CD8⁺ T-cells despite no change in the frequency of circulating MDSCs or T-regs after the first treatment cycle [313]. Although no association was observed between MDSC or T-reg levels and treatment response, an inverse trend in patient PFS and MDSC and T-reg frequency was observed but was not statistically significant [313]. Cancer vaccines can augment tumor-specific immunity, but it is hypothesized that their use would be most effective in patients with low MDSC frequency [303, 304, 306, 307, 310–313]. The mixed responses to vaccine-based immunotherapy describe a need for therapeutic strategies involving a combination of vaccine and other immune-modulating agents to abrogate the immunosuppressive effects of MDSCs and ensure the ability to mount sufficient T-cell anti-tumor responses. A phase II study on Sipuleucel-T with indoximod, an indoleamine 2,3-dioxygenase inhibitor (IDO) (NCT01560923) in prostate cancer patients [314], documented better PFS compared with Sipuleucel-T plus placebo, indicating that the IDO inhibitor may lead to improved vaccine and clinical outcomes. [315] This is based on the function of the tryptophan catabolic enzyme iIDO1 that can act as a driver of tumor-mediated suppression. Currently, numerous approaches to reduce MDSCs to improve immune response are undergoing, [316] yet no consensus on the clinical benefit of inhibiting the immunosuppressive effectors of MDSC has been made. More optimized studies are still needed. Other studies demonstrated that the combination of chemotherapeutic drugs with vaccines could decrease MDSC numbers and lead to additive survival benefits in cancer patients [11, 317]. Studies on combination trials of chemotherapeutic drugs to decrease MDSCs with vaccines include gemcitabine pretreatment to enhance the efficacy of DC vaccines after tumor resection by eliminating immunosuppressive cells. Additive effects of DC vaccines and gemcitabine are under investigation in adults and children with sarcoma (NCT01803152). Recently, a pilot study was conducted in eight metastatic RCC patients treated with autologous tumor lysate-loaded DC vaccine plus sunitinib. Analysis showed no vaccination-related severe adverse events. Moreover, tumor lysate-reactive T cell responses were observed in five patients, four of whom showed decreased frequencies of MDSCs. [318]

While ICIs are effective in reducing MDSCs, as demonstrated in patients with metastatic melanoma [289, 290, 294], their efficacy appears to be improved when given in combination with drugs targeting MDSCs. MDSCs inhibit T-cell activation and immune responses to tumor antigens [61, 92] despite the use of PD-1 and PD-L1 checkpoint inhibitors [169, 319]. Thus, therapeutic strategies promoting anti-tumor immune responses, i.e., ICIs, and ones that deplete or inhibit MDSCs may improve patient outcomes and reduce MDSC-associated ICI resistance [320]. A meta-analysis of anti-PD-1 therapy studies undertaken in NSCLC patients revealed that the addition of the PD-1 inhibitor pembrolizumab to chemotherapy resulted in significantly improved OS [321]. Similarly, combining the anti-angiogenic drug bevacizumab with the antimetabolite capecitabine was found to reduce circulating MDSCs following tumor resection [167]. Furthermore, in these studies, CyTOF analysis of tumor samples determined that adding capecitabine to the treatment regimen supported the induction of tumor-directed immune activation, with a significant reduction in the expression of CTLA-4 and PD-1 on macrophages and CTLA-4 on lymphocytes [167]. Preliminary studies from a phase I clinical trial using patients with metastatic tumors and the BTK inhibitor ibrutinib in combination with the PD-1 inhibitor nivolumab supported the use of the two inhibitors to significantly decrease plasma chemokine levels (IL-12, CCL2, CCL3, and CCL4) and circulating MDSCs as observed during the first cycle of therapy [322]. These studies support the efficacy of combining ICIs with immunomodulatory drugs and reinforce the approach of targeting MDSCs to improve the efficacy of ICI therapy.

In MM patients, PD-L1 expression is increased on plasma cells compared to the levels found on plasma cells from healthy donors, and its expression is associated with resistance to a variety of anti-MM treatments. The reported inhibition of the PD-L1/PD-1 pathway in plasma cells by ruxolitinib [323] and decreased G-MDSC (LOX-1 expression) in Hodgkin’s lymphoma treated with a PD-1 inhibitor plus ruxolitinib suggested that ruxolitinib may be used for combination therapy with ICI therapy in the treatment of myeloproliferative neoplasms (MPNs), as it can reduce MDSC expression of PD-L1. Further, MDSCs in MPN have an increase in PD-L1 expression, and ruxolitinib added to the CPI therapy may provide a promising treatment option. [324]

Summary

In summary, the goal of adjuvant therapy is to reduce the risk of recurrence and outgrowth of metastases after primary tumor treatment but must also constrain the release of tumor cells from dormancy. Tumor dormancy is a significant contributor to the time between initial diagnosis and relapse/metastasis following primary surgery and adjuvant therapy. Thus, improving our understanding of why DTCs enter dormancy, later reawaken, and proliferate into an occult metastasis and approaches to control this process is vital to developing effective therapeutic strategies against neoplastic disease. Dormant DTCs are rarely detectable with current diagnostic technologies, making it critical to better understand reawakening and preventing their outgrowth. Adaptive anti-tumor immune responses can maintain tumor cell dormancy, whereas chronic inflammation, i.e., circulating MDSCs, can reactivate DTC from immune-mediated dormancy. Thus, we suggest that limiting the expansion and function of MDSCs may maintain DTC dormancy and inhibit outgrowth of micro-metastases, resulting in prolonged survival. In conclusion, disrupting immune TME interactions provides an attractive therapeutic option, bringing us closer to the goal of preventing tumor relapse and improving patient quality of life.

This is not an inclusive list of drugs believed to decrease MDSC numbers and function. Rather, it is a list of drugs that have been studied clinically, frequently off label, and have been shown to have or potentially have clinical activity on MDSCs. AE, adverse event; ALVAC, cancer vaccine containing a canary pox virus; AML, acute myeloid leukemia; ARG1, arginase 1; ATRA, all-trans retinoic acid; BC, breast cancer; BM, bone marrow; BTK, Bruton’s tyrosine kinase; CA, cancer; CCL, chemokine ligand; CD, cluster of differentiation; CCL, chemokine (C–C motif); CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CRC, colorectal carcinoma; CRPC, castration-resistant prostate cancer; CSF-1R, colony stimulating factor-1 receptor; CRPC, CTL: cytotoxic T-lymphocyte; CTLA-4, CTL-associated protein 4; CXCR4, CXC chemokine receptor 4; DC, dendritic cell; DFS, disease-free survival; FOLFOX, folic acid, 5-fluorouracil, oxaliplatin; G, granulocyte; GBM, glioblastoma multiforme; GM, granulocyte–macrophage; HLA-DR, human leukocyte antigen-DR isotype; HNSCC, head and neck squamous cell carcinoma; Iba-1, ionized calcium-binding adaptor molecule 1; i, immature; IFN-g, interferon-gamma; IL, interleukin; iNOS, inducible nitric oxide synthetase; JAK, Janus kinase; L-NMMA, L-N(G)-monomethyl arginine acetate; Lin, linage; m, metastatic; M, macrophage; MDS, myeloid dysplastic syndrome; MDSC, myeloid-derived suppressor cell; MM, multiple myeloma; MVA, modified vaccinia virus Ankara; NO, nitric oxide; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PB, peripheral blood; PBL, peripheral blood leukocyte; PBMC, peripheral blood mononuclear cell; PD-1, programmed cell death; PDAC, pancreatic ductal adenocarcinoma; PDE-5, phosphodiesterase type 5; PD-L1, programmed death-ligand 1; PFS, progression-free survival; pt(s), patient(s); RCC, renal cell carcinoma; SCLC, small cell lung cancer; STAT, signal transducer and activator of transcription; TCR, T-cell receptor; TK, tyrosine kinase; TNBC, triple negative breast cancer; T-reg, T-regulatory cell; TX, transplant; UC, urothelial carcinoma; VEGF, vascular endothelial growth factor; ZA, zoledronic acid.

Abbreviations

5-FU: 5-Fluorouracil
ALL: Acute lymphoblastic leukemia
PDAC: Adenocarcinoma
AEs: Adverse events
ATRA: All-trans retinoic acid
ADCC: Antibody-dependent cellular cytotoxicity
ARG1: Arginase-1
BSC: Best supportive care
BM: Bone marrow
BTK: Bruton’s tyrosine kinase
CRC: Colorectal carcinoma
CLL: Chronic lymphocytic leukemia
CML: Chronic myeloid leukemia
CTCs: Circulating tumor cells
CD: Cluster of differentiation
CSFs: Colony-stimulating factors
CTL-4: CTL-associated protein 4
CXCR4: CXC chemokine receptor 4
cGMP: Cyclic guanosine monophosphate
COX2: Cyclooxygenase-2
CTLs: Cytotoxic T-lymphocytes
TAM: Tumor-associated macrophages
DC: Dendritic cells
DTCs: Disseminated tumor cells
AC: Doxorubicin plus cyclophosphamide
DCIS: Ductal carcinoma in situ
ENA-78/CXCL5: Epithelial neutrophil-activating peptide-78
ECM: Extracellular matrix
EMM: Extramedullary myelopoiesis
Flt-3: Fms-related tyrosine kinase 3
FOLFIRI: Folic acid, 5-FU, and irinotecan
FOLFOX: Folic acid, 5-FU, and oxaliplatin
FDA: Food and Drug Administration
GemCap: Gemcitabine with capecitabine
GBM: Glioblastoma multiforme
G-CSF: Granulocyte-colony stimulating factor
GM: Granulocyte macrophage
G: Granulocytic
HNSCC: Head and neck squamous cell carcinoma
HPC: Hematopoietic progenitor cell
HSCs: Hematopoietic stem cells
ITK: IL-2-inducible kinase
i or e: Immature or early
ICIs: Immune checkpoint inhibitors
ir: Immune response
IFN: Interferon
IL-2: Interleukin-2
JAK: Janus kinase
Lin −: Lineage-negative
LAG-3: Lymphocyte activation gene-3
MNK1/2: MAPK-interacting serine/threonine protein kinases 1 and 2
CyTOF: Mass cytometry time of flight
MMPs: Matrix metalloproteinases
MRD: Minimal residual disease
MAPK: Mitogen-activated protein kinase
M: Monocytic
MM: Multiple myeloma
MDSC: Myeloid-derived suppressor cells
MPCs: Myelopoietic progenitor cells
NK: Natural killer
NOS2: Nitric oxide synthase
NSCLC: Non-small cell lung cancer
OS: Overall survival
PDAC: Pancreatic ductal adenocarcinoma
PEGylated G-CSF: Peg-filgrastim
PBMCs: Peripheral blood mononuclear cells
PDE5: Phosphodiesterase type 5
PMN: Polymorphonuclear
PD1: Programed death
PD-L1: Programmed death-ligand 1
PFS: Progression-free survival
PGE2: Prostaglandin E2
ROS: Reactive oxygen species
RCC: Renal carcinoma
RECIST: Response Evaluation Criteria in Solid Tumors
RET: Ret proto-oncogene
Rux: Ruxolitinib
M-protein: Serum monoclonal immunoglobulin
sFAS-L: SFAS ligand
STAT: Signal transducer and activator of transcription
STAT3: Signal transducer and activator of transcription 3
SCLC: Small cell lung cancer
sFAS: Soluble FAS
SDF-1/CXCL12: Stromal cell-derived factor 1
TCR- ζ: T-cell receptor zeta chain
TLR: Toll-like receptor
T-regs: T-regulatory cells
TME: Tumor microenvironment
TANs: Tumor-associated neutrophils
TKI: Tyrosine kinase inhibitor
VEGF: Vascular endothelial growth factor
VEGFR1 +: Vascular endothelial growth factor receptor-1 positive
VDR: Vitamin D receptor
ZA: Zoledronic acid

Author contribution

All the authors have participated in the writing of this submission and reviewed and approved the submission of this manuscript.

Funding

This work was supported, in whole or in part, by National Institutes of Health Grants for Specialized Programs of Research Excellence (Grant P50 CA127297) and by the Fred & Pamela Buffett Cancer Center Support (Grant P30 CA036727).

Declarations

Ethics approval

As this was a review, no animal or human specimens were involved in the writing of the review.

Conflict of interest

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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PERMALINK

Role of myeloid-derived suppressor cells in tumor recurrence

Kathryn Cole

Zaid Al-Kadhimi

James E Talmadge

Abstract

Introduction

Fig. 1.

Timing and processes of tumor metastasis initiation and progression

MDSCs and metastasis

Dormancy of micro-metastatic foci

MDSCs, pre-metastatic niches, and release from metastatic dormancy

Therapeutic regulation of MDSCs in neoplasia

Table 1.

Chemotherapy-associated depletion and inhibition of MDSC proliferation

Attenuation of MDSC function

Inhibition of MDSC recruitment

Induction of MDSC differentiation

Tyrosine kinase and JAK inhibitors

Overview of combining MDSC inhibition with immunotherapy

Summary

Abbreviations

Author contribution

Funding

Declarations

Ethics approval

Conflict of interest

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Role of myeloid-derived suppressor cells in tumor recurrence

Kathryn Cole

Zaid Al-Kadhimi

James E Talmadge

Abstract

Introduction

Fig. 1.

Timing and processes of tumor metastasis initiation and progression

MDSCs and metastasis

Dormancy of micro-metastatic foci

MDSCs, pre-metastatic niches, and release from metastatic dormancy

Therapeutic regulation of MDSCs in neoplasia

Table 1.

Chemotherapy-associated depletion and inhibition of MDSC proliferation

Attenuation of MDSC function

Inhibition of MDSC recruitment

Induction of MDSC differentiation

Tyrosine kinase and JAK inhibitors

Overview of combining MDSC inhibition with immunotherapy

Summary

Abbreviations

Author contribution

Funding

Declarations

Ethics approval

Conflict of interest

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

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