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Published in final edited form as: Trends Pharmacol Sci. 2022 Oct 26;43(12):1085–1097. doi: 10.1016/j.tips.2022.09.009

Atypical chemokine receptors: Emerging therapeutic targets in cancer

Robert J Torphy 1, Elliott J Yee 1, Richard D Schulick 1, Yuwen Zhu 1
PMCID: PMC9669249  NIHMSID: NIHMS1839862  PMID: 36307250

Abstract

Atypical chemokine receptors (ACKRs) regulate the availability of chemokines via chemokine scavenging, while also having the capacity to elicit downstream function through β-arrestin coupling. This contrasts with conventional chemokine receptors that directly elicit immune cell migration through G protein-coupled signaling. The significance of ACKRs in cancer biology has previously been poorly understood, but recent findings have highlighted the multifaceted role of these receptors in tumorigenesis and immune response modulation within the tumor microenvironment. Additionally, recent research has expanded our understanding of the function of several receptors including GPR182, CCRL2, GPR1, PITPNM3, and C5aR2 that share similarities with the ACKR family. In this review, we discuss these recent developments, and highlight the opportunities and challenges of pharmacologically targeting ACKRs in cancer.

Keywords: atypical chemokine receptor, G protein-coupled receptor, chemokine, cancer, immunotherapy, arrestin-coupled receptors

Chemokine and Atypical Chemokine Receptors in Cancer

Cancer remains a leading cause of death despite significant progress in cancer diagnosis and treatment [1]. Over the past two decades, the advent of immunotherapy has significantly improved cancer outcomes and immune checkpoint therapy is now part of the standard of care in the treatment of multiple malignancies [2]. While immunotherapy is very successful in certain cancers, many tumors are unresponsive to immunotherapy due to an immunosuppressive tumor microenvironment (TME) which prevents an effective antitumor immune response [3]. Chemokines and conventional chemokine receptors have received great attention as therapeutic targets in cancer because of their integral role in controlling the migration of immune cells and regulating the immune cell composition within the TME [4, 5]. Currently, a small molecule inhibitor of CXCR4 (Plerixafor) and a monoclonal antibody targeting CCR4 (Mogamulizumab) are in clinical use targeting conventional chemokine receptors in cancer with numerous others in preclinical development and clinical trials [4, 6, 7].

Atypical chemokine receptors (ACKRs) are a subfamily of chemokine receptors that includes ACKR1 (DARC), ACKR2 (D6), ACKR3 (CXCR7), and ACKR4 (CCRL1 or CCX-CKR) [8]. They have received less attention as therapeutic targets in cancer as their biologic function has been less well understood. ACKRs were previously thought to only function as “decoy” or “scavenger” receptors due to their capacity to bind chemokines without eliciting downstream G protein-coupled signaling [9], which primarily differentiates them from conventional chemokine receptors. However, recent findings have uncovered a significant role of ACKRs in cancer biology [10]. Cancer cell expression of ACKRs can mediate tumor growth and metastasis [11, 12] and stromal cell expression of ACKRs can mediate antitumor immunity in the TME [13]. Recent research has also expanded our understanding of the function of several receptors that share similarities with the ACKR family and play important roles in tumor biology [14–19]. The expanding knowledge of the biologic function of ACKRs in cancer and the recent identification of additional receptors with atypical properties highlights the importance of further investigating this family of receptors as therapeutic targets in cancer. Importantly, the role of ACKRs in shaping the immune landscape within the TME provides novel opportunities to target ACKRs in combination with immunotherapy to improve response rates in tumors with immunosuppressive microenvironments [13, 17]. In this review, we will provide an overview of the biology of ACKRs with a focus on newly identified chemokine receptors with atypical properties, summarize the emerging role of ACKRs in cancer, and highlight the opportunities and challenges of pharmacologically targeting ACKRs in cancer therapy.

Overview of ACKR Biology

ACKRs and conventional chemokine receptors share the common trait of binding chemokines; however, ACKRs have distinct biologic characteristics that differentiate them from the conventional chemokine receptors. While conventional chemokine receptors are primarily expressed by immune cells and promote immune cell movement through G protein-coupled signaling, ACKRs are expressed on diverse cell types including blood and lymphatic endothelium cells (BEC and LEC, respectively), coordinate immune cell trafficking through chemokine scavenging, and are biased towards β-arrestin coupling (Figure 1) [5, 9, 20].

Figure 1. Biologic characteristics differentiating conventional and atypical chemokine receptors.

Figure 1.

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Conventional chemokine receptors and ACKRs both bind chemokines; however, they differ in cellular expression patterns and function. (A) Conventional chemokine receptors are expressed primarily by immune cells and couple to intracellular G proteins. Upon ligand binding, heterotrimeric G proteins are activated and stimulate down-stream signaling cascades. A key biologic outcome of chemokine binding to conventional chemokine receptors is stimulating direction cell movement along chemokine gradients. (B) In contrast to conventional chemokine receptors, ACKRs are expressed by diverse cell types, with endothelial cell expression being most common. Upon chemokine binding, ACKRs act to scavenge their chemokine ligands through endocytosis, chemokine degradation, or transcytosis of bound chemokine to the contralateral cell surface. This chemokine scavenging function acts to shape chemokine gradients and thus indirectly control immune cell migration. (C) In addition to purely scavenging chemokines, ACKRs can couple with β-arrestin. β-arrestin coupling can occur constitutively or upon chemokine binding and result in the stimulation of down-stream signaling or receptor internalization.

Expression of ACKRs on diverse cell types including blood and lymphatic endothelium

A key characteristic of ACKRs is their expression by diverse cell types, often including blood and lymphatic endothelium, as well as various immune cell populations (Figure 2A) [20–28]. This contrasts with conventional chemokine receptors that are primarily expressed by immune cells [5]. The expression of ACKRs on endothelium is integral to their role in shaping chemokine gradients as this is a key site of migration of immune cells between blood or lymph and peripheral tissues [29].

Figure 2. The atypical chemokine receptor family and additional atypical receptors.

Figure 2.

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Summary of the ACKR family including the current (ACKR1-ACKR4) members (A) and additional atypical receptors (GPR182, CCRL2, GPR1, PITPNM3, C5aR2) (B). Th expression patterns, ligands, and function are summarized. PAMP: Proadrenomedullin N-Terminal 20 Peptides; BEC: Blood endothelial cell; LEC: Lymphatic endothelial cell; SEC: Sinusoidal endothelial cell; NK Cell: Natural killer cell.

Coordination of immune cell trafficking through chemokine scavenging

A second unifying characteristic of ACKRs is their ability to indirectly regulate immune cell trafficking through chemokine scavenging. Conventional chemokine receptors bind chemokines and elicit directional cell movement through Gαi mediated signaling resulting in cell migration along chemokine gradients (Figure 1A) [5, 9, 20]. In contrast, the ACKRs do not trigger G protein-coupled signaling following chemokine binding of their respective ligands, but instead shape chemokine gradients through ligand endocytosis, transcytosis, or degradation (Figure 1B) [20–28, 30, 31]. By shaping chemokine gradients and helping to control the local concentrations of chemokines, ACKRs indirectly coordinate the movement of immune cells.

The function of each of the ACKRs in coordinating immune cell trafficking is well described. On BECs, ACKR1 functions to transcytose chemokines and establish gradients that promote immune cell migration at sites of local inflammation [22]. Similarly, in neuronal microvasculature, ACKR3 promotes leukocyte passage into the central nervous system [26]. On LECs, ACKR2 promotes the resolution of inflammation through scavenging inflammatory chemokines [23, 24], and ACKR4 facilitates the creation of CCL19 and CCL21 gradients which are integral in dendritic cell and naïve T cell trafficking in secondary lymphoid tissues [27, 32].

While our understanding of ACKR biology has largely focused on their role in scavenging chemokines, ACKRs can also couple with β-arrestin and stimulate various downstream signaling pathways [33, 34].

Bias towards β-arrestin coupling

The last key characteristic of ACKR biology is their bias towards β-arrestin coupling [33]. A conserved function of G protein-coupled receptors is their ability to promote downstream signaling through coupling with heterotrimeric G proteins following ligand binding [35]. This G protein-coupled signaling is triggered in conventional chemokine receptors following binding to cognate chemokine ligands [33]. In addition to signaling through G proteins, ligand binding to G protein-coupled receptors can stimulate β-arrestin recruitment, which can lead to receptor internalization or trigger distinct downstream signaling pathways [34, 35]. ACKRs are unique amongst G protein-coupled receptors as they do not couple with heterotrimeric G proteins following ligand binding and are strongly biased towards β-arrestin coupling (Figure 1C) [33, 36]. Recent research proposes that the structural features of the intracellular loops of ACKRs, which have similarities to partially activated G protein-coupled receptors, drive their bias towards β-arrestin coupling [36].

Our understanding of the full biologic significance of β-arrestin coupling in ACKRs is still growing. ACKR2, ACKR3, and ACKR4 have all been shown to interact with β-arrestin (Figure 2A) [19, 33]. While β-arrestin coupling can promote receptor desensitization through receptor internalization, β-arrestin coupling does not appear to be necessary for ACKR endocytosis and chemokine scavenging. Furthermore, β-arrestin coupling can occur constitutively, in the absence of chemokine binding [37, 38]. Uncovering the full biologic significance of β-arrestin coupling by ACKRs in cancer is an important area of future research.

While the ACKR family has been formally recognized as consisting of ACKR1-4 [8], recent research has identified additional receptors that share some or all of the atypical biologic characteristics of ACKRs suggesting this family of receptors may be expanding [14–18, 39].

Expanding the ACKR Family

Recent research has expanded our understanding of the function of several receptors including GPR182, CCRL2, GPR1, PITPNM3, and C5aR2 that share similarities with the ACKR family including diverse cellular expression patterns, ligand scavenging, and β-arrestin biased coupling. (Figure 2B) (Box 1) [14–18, 39].

Box 1: Expanding the ACKR family- Receptors with atypical properties.

GPR182

  • Broadly binds and scavenges chemokines [16, 17].

  • Expressed by blood endothelial cells (microvasculature, sinusoidal endothelium in liver and spleen) and lymphatic endothelial cells [40–43]. Its expression is also upregulating on tumor lymphatics [17, 44].

  • Undergoes constitutive β-arrestin recruitment and ligand independent internalization [16, 17, 45].

CCRL2 and GPR1

  • G protein-coupled receptors with close homology to the chemokine receptor family [39, 71].

  • No known chemokine ligand. Bind chemerin, a non-chemokine chemoattractant.

  • CCRL2 immobilizes chemerin on the cell surface helping to increase its local bioavailability [72, 73]. Does not elicit downstream G protein-coupled signaling or β-arrestin recruitment upon chemerin binding [74].

  • GPR1 recruits β-arrestin upon ligand binding and leads to receptor internalization and scavenging of chemerin [39]

PITPNM3

  • Chemokine receptor that is a member of the phosphatidyl-inositol transfer protein (PITP) and not homologous to the other chemokine receptors that belong the G protein-coupled receptor family [8].

  • Binds CCL18 and promotes cellular migration in a CCL18-dependent manner [15, 51, 75].

  • Through directly promoting cellular chemotaxis, PITPNM3 functions similarly to a conventional chemokine receptor.

  • PITPNM3 has not been shown to internalize CCL18 upon binding, and thus does not have the same scavenger function as the other ACKRs.

C5aR2

  • Has no known chemokine ligands. Functions as a receptor in the complement system for C5a, which is a key complement peptide produced during activation of the complement system [18, 76].

  • Unable to elicit G protein-coupled signaling upon ligand binding and biased towards β-arrestin coupling [18, 34].

  • Functions to scavenge and degrade its ligand, C5a function of internalizing bound ligand resulting in their intracellular degradation [77].

Foremost among these receptors is GPR182, which is the most recent receptor to be proposed as an additional member of the ACKR family and demonstrates all the key characteristics of the known ACKRs [16, 17]. GPR182 is expressed on endothelial cells, including LECs, microvascular endothelial cells, and sinusoidal endothelial cells (SECs) in the liver and the spleen [40–43]. Its expression is also upregulated on tumor lymphatics [17, 44]. GPR182 broadly binds chemokines with varying degrees of affinity [16, 17]. Interestingly, GPR182 directly interacts with the glycosaminoglycan-binding motif within chemokines, which mediates their attachment to endothelium or the extracellular matrix [17]. GPR182 undergoes constitutive β-arrestin coupling and ligand independent internalization [16, 17, 45]. In the presence of chemokine ligands, this results in rapid chemokine endocytosis and transport of chemokines to intracellular endosomes [17]. In GPR182- deficient mice, serum levels of the chemokines CXCL10, CXCL12 and CXCL13 are systemically elevated, demonstrating the physiologic relevance of GPR182’s scavenging function [16].

Our growing understanding of the biologic function of the ACKRs and these additional receptors that share the atypical biologic characteristics of ACKRs has led to exciting discoveries of the role these receptors play in cancer and their potential as therapeutic targets.

Emerging Roles of ACKRs in Cancer

While early research into the significance of ACKRs in cancer revealed associations between ACKR expression and cancer outcomes, more recent work has provided concrete mechanistic evidence for the significance ACKRs play cancer biology [46]. Our current understanding indicates ACKRs play two roles in cancer progression. First, cancer-associated stromal cell expression of ACKRs alters the immune response within the TME through chemokine scavenging and regulation of immune cell homing (Figure 3) [13, 17, 19, 47–49]. Secondly, ACKR expression by cancer cells directly impacts tumorigenesis (Figure 4) [11, 12, 15, 50–52].

Figure 3. Regulation of tumor immunity by atypical chemokine receptors.

Figure 3.

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(A) ACKR4 scavenges the chemokines CCL19 and CCL21 in the tumor microenvironment. This chemokine scavenging helps to control the bioavailability of these chemokines which is important for the coordination of dendritic cell migration from tumors to lymphatics and tumor draining lymph nodes. (B) GPR182 scavenging the chemokines CXCL9 and CXCL10 in the tumor microenvironment reducing their abundance. The reduction in these chemokines within the tumor impairs effector T cell homing to tumors. (C) CCRL2 is expressed by both tumor associated macrophages and endothelial cells in the tumor microenvironment. CCRL2 promotes polarization of macrophages to an activated phenotype which promotes antitumor immunity. Endothelial CCRL2 binds chemerin on the surface of endothelial cells and promotes NK cell recruitment to tumors.

Figure 4. Cancer cell intrinsic effects of atypical chemokine receptors on several hallmarks of cancer.

Figure 4.

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(A) ACKR3 binds to CXCL12 which results in downstream intracellular signaling through β-arrestin and promotes cellular proliferation and tumor growth. (B) ACKR2/CXCL14 and PITPNM3/CCL18 interactions promote epithelial to mesenchymal transition of cancer cells resulting in increased capacity for invasion and metastasis. (C) CCRL2 on tumor cells binds chemerin. The increased concentration of chemerin bound to CCRL2 in the TME inhibits tumor angiogenesis.

ACKR expression by stromal cells alters the immune response within the TME through chemokine scavenging and regulation of immune cell homing

The TME is composed of a variety of non-cancerous stromal cell types, such as endothelial cells, fibroblasts, and a milieu of immune cells, that contribute to the biology of a tumor. The expression of ACKRs by various stromal cell populations plays an active role in shaping the local immune response through modulating chemokine bioavailability (ACKR4, GPR182, and CCRL2) [13, 17, 47] and directly regulating immune cell migration (CCRL2) [19].

ACKR4 is one example of an ACKR that mediates immune cell trafficking in the TME via its expression on stromal cells. ACKR4, mainly expressed on LECs and fibroblasts, binds and scavenges CCL19 and CCL21, which are ligands for the conventional chemokine receptor CCR7 expressed on dendritic cells and T cells [32, 53]. Through regulation of CCL19 and CCL21 bioavailability in the TME, ACKR4 mediates the emigration of tumor dendritic cells to lymphatics and tumor draining lymph nodes (Figure 3A) [54]. In ACKR4-knockout mice, dendritic cell migration is disrupted in the TME resulting in enhanced antitumor immunity in multiple tumor models [13]. It is thought that the loss of stromal ACKR4 results in increased intra-tumoral CCL21 levels and promotes the retention of dendritic cells in the TME. In turn, this leads to increased cross presentation of tumor antigens to CD8+ T cells and results in a more robust antitumor T cell response [13, 55].

While ACKR4 alters dendritic cell migration and T cell activation within tumors, GPR182 has a role in regulating T cell homing to tumors [17]. In both human and murine melanoma models, GPR182 was found to be upregulated on LECs [17]. In GPR182-knock out mice, effector T cell infiltration into the TME is increased, resulting in reduced tumor growth. Mechanistically, this is thought to be due to GPR182’s chemokine scavenging function resulting in a reduction of CXCL9 and CXCL10 concentrations within the TME, thereby diminishing the migration of T cells to tumors (Figure 3B). This finding aligns with past work that demonstrated the importance of the chemokines CXCL9 and CXCL10 in the migration of effector T cells to tumors [56].

Unlike ACKR4 and GPR182 that appear to dampen the immune response in the TME through chemokine scavenging, CCRL2 acts to enhance antitumor immunity by directly promoting immune cell migration into the TME (Figure 3C). In a murine lung cancer model, tumors of CCRL2-knockout mice were significantly larger compared to control tumors. Analysis of cell populations within the TME revealed significantly reduced infiltration of natural killer (NK) cells in the TME of CCRL2-knockout mice [47]. CCRL2 expression in the TME was confirmed to be limited to endothelial cells suggesting loss of CCRL2 impairs NK cell recruitment into lung tumors. The authors hypothesized the effect of CCRL2 on the migration of NK cells was due to CCRL2’s ability to bind and concentrate chemerin on endothelial cells which acts a chemoattractant to promote NK cell migration [47]. In addition to its role in regulating NK cell homing, CCRL2 has also been shown to be expressed on tumor infiltrating macrophages. CCRL2 expression in preclinical melanoma models is associated with immunostimulatory polarization of macrophages to a M1 phenotype which promotes a heightened antitumor immune response [19].

ACKR expression by cancer cells directly impacts tumorigenesis

In addition to their expression on stromal cell populations and regulation of the immune microenvironment within tumors, ACKRs can also be upregulated on cancer cells and directly impact tumorigenesis [46]. ACKR2, ACKR3, PITPNM3 and CCRL2 have been implicated in tumorigenesis as they help regulate multiple hallmarks of cancer including cell proliferation, migration and metastasis, and tumor angiogenesis (Figure 4) [11, 12, 15, 50–52, 57, 58].

The expression of ACKR3 by various types of cancers has been implicated in promoting tumorigenesis though directly impacting cell proliferation and survival (Figure 4A) [11, 52, 58]. In melanoma, high ACKR3 expression was observed to be associated with worse overall survival, and in preclinical models, ACKR3 expression promoted melanoma growth. This cancer cell intrinsic pro-tumorigenic effect of ACKR3 was demonstrated to be mediated by CXCL12 induced signaling downstream of β-arrestin [11]. Similarly, in prostate cancer, ACKR3 can induce β-arrestin mediated signaling to promote tumor growth and resistance to first- and second-line therapies [52]. CCX771 is an agonist of ACKR3 and competes with other ligands for binding to ACKR3 [59]. Targeting ACKR3 with CCX771 in mouse models of prostate cancer that are resistant to first- and second-line therapies has shown great promise in a recent preclinical study [60].

While ACKR3 directly effects tumor growth, ACKR2 and PITPNM3 have been implicated in mediating cancer migration and metastasis (Figure 4B) [12, 15, 51]. Using both in vivo and in vitro models, ACKR2 was demonstrated to mediate the effects of fibroblast derived CXCL14 in supporting cancer cell migration and metastasis downstream of MAPK (mitogen-activated protein kinase) signaling [12]. The ACKR2/CXCL14 interaction promoted epithelial-to-mesenchymal transition (EMT) and enhanced migration and invasion of breast cancer cells [12]. PITPNM3 has similarly been shown to promote EMT, invasion, and metastasis in breast cancer and hepatocellular carcinoma through its interaction with CCL18 [15, 51]. A small molecule inhibitor of PITPNM3 has recently been identified that prevents CCL18/PITPNM3 mediated signaling. This inhibitor has shown efficacy in inhibiting CCL18 induced migration of breast cancer cells in vitro and further preclinical testing is ongoing [61]. Directly targeting ACKR intrinsic effects on tumorigenesis is a promising anti-cancer strategy.

Unlike ACKR2, ACKR3, and PITPNM3 that directly mediate their effects on cancer growth and invasion, cancer cell expression of CCRL2 has also been shown to modulate cancer growth through its effect on angiogenesis in the TME [50]. Overexpression of CCRL2 in murine melanoma and lung cancer resulted in reduced tumor outgrowth and decreased tumor angiogenesis [50]. Similar to its role in regulating intratumoral NK cell migration, CCRL2’s ability to reduce tumor angiogenesis is thought to be secondary to binding and concentrating host-produced chemerin in the TME. (Figure 4C) [50].

Opportunities for Transforming Immunologically “Cold” Tumors to Immunologically “Hot” Tumors Through Targeting ACKRs

In addition to directly targeting ACKR intrinsic effects on tumorigenesis, possibly the most promising area of ACKR targeted therapies in cancer treatment is modulating the immune response in the TME in conjunction with immunotherapy. Immune checkpoint blockade therapies, particularly targeting PD-1 and CTLA-4, have been the most successful immunotherapies for solid organ malignancies [62]. Unfortunately, a significant population of patients fail to respond to immunotherapy due to poor T cell infiltration into the TME [63]. These tumors that fail to respond due to poor T cell infiltration are thought of as “immunologically cold,” while tumors with robust T cell infiltration that demonstrate response to immunotherapy are “immunologically hot [63].” Targeting ACKRs represents an exciting new approach towards improving the efficacy of immunotherapy as it offers a novel mechanism for enhancing T cell infiltration and activation in tumors and may therefore sensitize tumors to immune checkpoint blockade that would otherwise be resistant.

The potential efficacy of targeting ACKRs in combination with conventional immunotherapy was first demonstrated in ACKR4-knockout mice [13]. Using the B16 murine melanoma model that is poorly responsive to immune checkpoint blockade due to poor T cell infiltration into the TME, loss of ACKR4 sensitized tumors to immune checkpoint blockade with anti-PD-1 and anti-CTLA-4 therapy. Analysis of the stromal cell populations in the TME demonstrated that ACKR4 was predominantly expressed by fibroblasts, which was also the primary source of CCL21 production [13]. Loss of ACKR4 expression and scavenging function in the TME resulted in increased levels of CCL21 in tumors, increased retention of dendritic cells in the TME, and ultimately promoted more effective T cell priming and antitumor immunity (Figure 5A) [13].

Figure 5. Opportunities for transforming immunologically “cold” tumors to immunologically “hot” tumors through targeting atypical chemokine receptors.

Figure 5.

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(A) Fibroblast ACKR4 scavenges CCL21 in the tumor microenvironment (TME) and promotes emigration of dendritic cells to tumor draining lymphatics. Therapeutically targeting ACKR4 can increase CCL21 concentration in the tumor microenvironment resulting in retention of antigen presenting dendritic cells within tumors and increased accumulation and activation of T cells in the tumor microenvironment. (B) Endothelial GPR182 scavenges CXCL9 and CXCL10 in the tumor microenvironment. Therapeutically targeting GPR182 can increase levels of CXCL9 and CXCL10 in the tumor, and in turn, promoting more robust infiltration of effector T cells into the tumor microenvironment.

GPR182 is another promising target in conjunction with immunotherapy due to its role in scavenging CXCL9 and CXCL10, which are primarily produced by dendritic cells and macrophages [64]. Loss of endothelial GPR182 leads to increased levels of CXCL9 and CXCL10 in the TME of murine melanoma, which in turn, results in increased homing of effector CD4+ and CD8+ T cells to tumors [17]. Loss of GPR182 effectively sensitized two models of murine melanoma to both immune checkpoint blockade and adoptive T cell therapy (Figure 5B) [17].

Targeting ACKR4 and GPR182 to convert “immunologically cold” tumors to “immunologically hot” may help to expand the clinical utility of immunotherapy to tumors that historically have been unresponsive to immunotherapy.

Challenges of Pharmacologically Targeting ACKRs: Multifunctionality versus Specificity of ACKRs and the Chemokine System

Proposed obstacles in targeting ACKRs and conventional chemokine receptors include the multifunctionality and redundancy of these receptors in the human body and challenges in drug design [65–67]. The chemokine receptor system is described as promiscuous or redundant because many chemokine receptors bind multiple chemokine ligands and vice versa [68]. The ACKR family demonstrates similar redundancy in ligand binding as some ligands bind different receptors (Figure 2). This overlap in receptor-ligand interactions suggests a need to target multiple receptors or ligands simultaneously to achieve a therapeutic outcome. However, as ongoing research continues to shed light on the chemokine system, there appears to be less physiologic redundancy than previously thought as specificity may ultimately be determined by contextual, spatial, and temporal effects [69, 70]. The tissue specific expression of ACKRs and their upregulation in the settings of inflammation and malignancy offer specificity that may aid in effective therapeutic strategies.

Concluding Remarks and Future Perspectives

The ACKR family is a unique subset of chemokine receptors capable of profoundly influencing cancer biology and tumor immunity. ACKRs thus hold great potential as therapeutic targets to directly limit tumor growth and metastasis as well as being targeted synergistically with conventional immunotherapy. Nonetheless, several key questions remain unanswered that will need to be addressed for further progress to be made in therapeutically targeting ACKRs (See Outstanding Questions). Much of the work to date on understanding the function of ACKRs in cancer has utilized genetically modified animals deficient in the receptor of interest or genetically modified tumor cell lines. As preclinical pharmacologic agents targeting ACKRs are developed, it will be important to evaluate if these agents have the same robust effects compared to genetic deletion of the receptor. Additionally, will therapeutically targeting ACKRs be able to overcome the natural redundancy of the chemokine system? The multifunctionality of the ACKR and chemokine receptor system may pose an obstacle in effectively targeting the ACKR family, but this innate redundancy and tissue specific expression of ACKRs may help limit off target side effects. In the context of targeting ACKRs in combination with immunotherapy, will immune related side effects be more severe than with immunotherapy alone? The next integral step in moving the field forward will be the development of small molecule inhibitors or antibodies to therapeutically target ACKRs in humans to begin translating these exciting preclinical results to patient care.

Outstanding Questions.

  1. Can ACKRs be effectively targeted to improve the efficacy of conventional immunotherapies in historically immunologically “cold” tumors?

  2. Can ACKRs be targeted to directly treat tumor growth and invasion?

  3. Can we develop pharmacologic agents to target ACKRs with similar results as demonstrated in knockout mouse models?

  4. Can the natural redundancy of the chemokine and chemokine receptor be an obstacle for the efficacy of ACKR targeted therapy or help limit off target side effects?

  5. In the context of targeting ACKRs in combination with immunotherapy, will immune related side effects be more severe than with immunotherapy alone?

  6. Will pharmacologically targeting ACKRs with small molecule inhibitors or antibodies be more effective?

Highlights.

  • ACKRs are a subgroup of the chemokine receptor family that can bind and scavenge chemokine ligands via endocytosis or transcytosis.

  • ACKRs do not couple to G proteins but can elicit downstream cellular processes primarily via β-arrestin coupling.

  • Cancer cell expression of ACKRs can directly affect tumorigenesis, metastasis, and angiogenesis.

  • Several ACKRs are upregulated in stromal cells within the tumor microenvironment. Through chemokine scavenging, ACKRs help control the bioavailability of chemokines in the tumor microenvironment leading to alterations in immune cell activation and migration.

  • Therapeutically targeting ACKRs offers opportunities for inflaming immunologically cold tumors and thereby sensitizing them to immunotherapy.

Acknowledgments

This work was supported by NIH/NCATS Colorado CTSI Grant Number UL1 TR002535 (R.J.T.), NIH/1R01CA258302 (Y.Z.), and the Research Scholar Grant, RSG-17-106-01 LIB, from the American Cancer Society (Y.Z.). Figures were created with BioRender.com.

Glossary

Atypical chemokine receptors (ACKRs)

A subfamily of chemokine receptors that are expressed on diverse cell types, coordinate immune cell trafficking through chemokine scavenging, and are biased towards β-arrestin coupling.

β-arrestin

Intracellular proteins, including β-arrestin-1 and β-arrestin-2. Recruited to G protein-coupled receptors constitutively or upon receptor activation leading to receptor internalization, desensitization, or down-stream signaling.

Chemerin

A non-chemokine chemoattractant and the main ligand for CCRL2. Induces chemotaxis of several immune cell types through its interactions with chemokine-like receptor 1.

Chemokines

Cytokines that primarily promote chemotaxis or directional migration of immune cells.

Conventional chemokine receptors

G protein-coupled receptors that are primarily expressed by immune cell populations and bind chemokines. Conventional chemokine receptors signal through G-proteins following chemokine binding to induce the migration of immune cells along chemokine gradients.

Complement system

Network of soluble and cell surface proteins involved in the innate immune response to defend against pathogens.

Gαi mediated signaling

Upon ligand binding to a G protein-coupled receptor, the Gαi subunit is activated leading to inhibition of cyclic AMP production.

Hallmarks of cancer

Distinctive features that encompass the unique biologic features of cancer and together promote tumorigenesis and metastasis.

Immunotherapy

Approach to cancer treatment that helps promote the immune system’s ability to defend against cancer.

Immune checkpoint therapy

Type of immunotherapy which uses antibody drugs to turn off immunosuppressive signals and amplifying antitumor immunity.

Epithelial mesenchymal transition

Process of epithelial cells undergoing phenotypic transformation to a mesenchymal cell type with decreased cellular adhesion and increased invasive capacity. In the setting of cancer, this transition helps to facilitate tumor metastasis.

Glycosaminoglycan-binding motif

Chemokine structural element consisting of basic amino acids (arginine, lysine, histidine) that facilitate chemokine interaction with glycosaminoglycans which facilitates local retention of chemokines and the formation of chemokine gradients.

Stromal cell

Non-cancerous cell types including immune cells, fibroblasts, endothelial cells which are present in the tumor microenvironment.

T cell priming

The exposure of T cells to antigens that leads to the transformation of naïve T cells to effector T cells which promote cellular immunity.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Declaration of interests

R.J.T., R.D.S., and Y.Z. filed a provisional patent related to the GPR182 pathway.

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