Chemokine-chemokine receptor networks in conventional type I dendritic cells: An opportunity to prime and boost anti-cancer immunity

Abstract

Type I conventional dendritic cells (cDC1s) are key drivers of anti-tumor immunity. In human cancers, their presence correlates with better prognosis and survival benefits. In preclinical mouse tumor models, cDC1s are indispensable for successful T cell-mediated tumor killing and therapeutic response to immune checkpoint blockade (ICB) therapies. The essential role of cDC1s in anti-tumor immunity stems from their ability to uptake tumor-derived antigens and traffic them to the tumor-draining lymph node (tdLN) for T cell priming. At the tdLN, cDC1s present tumor antigens to naïve CD8⁺ T cells and polarize them into tumor-specific cytotoxic T cells that eventually kill the tumor cells. Within the tumor, cDC1s secrete the chemokines CXCL9 and CXCL10 that recruit CXCR3⁺ effector NK and T cells and thereby sustain a local cytotoxic T cell response. The trafficking and migration of cDC1s to the tumor and tdLNs are largely mediated by a chemokine-chemokine receptor network linking cDC1s to their interacting immune cell partners. In this review, we discuss two key chemokine ligand-receptor pairs, CCL5-CCR5 and XCL1-XCR1, that play essential roles in directing cDC1 migration to the tumor. Strategies that harness these cDC1-recruiting chemokine systems offer invaluable therapeutic prospects for enhancing current vaccine design and cancer immunotherapies.

Introduction

Dendritic cells (DC) are sentinel cells that bridge between innate and adaptive immunity. Prominently recognized as professional antigen-presenting cells, DCs are comprised of plasmacytoid DCs (pDCs) and conventional dendritic cells (cDCs). pDCs are major producers of the cytokine type I interferon (IFN-I) during viral infection¹. In tumors, IFN-I can directly induce apoptosis in tumor cells and indirectly promote the activation and proliferation of cytotoxic natural killer cells and CD8⁺ T cells that eliminate tumor cells^2,3. Two major cDC subsets have been identified in tumors: cDC1s, which are recognized as the most potent cross-presenting immune effectors, priming antigen-specific CD8⁺ T cells and correlating with favorable prognosis^4–6, and cDC2s, which present exogenous antigens to CD4⁺ T cells but lack consistent associations with cancer prognosis and treatment responses⁷. cDC1s play a pivotal role in anti-tumor immunity, whose importance was demonstrated in Batf3^−/− mice that lack cDC1s, and XCR1^DTRvenus mice^4,8–10, which enables depletion of XCR1-expressing cDC1 upon diphtheria toxin treatment^4,8–10. In these preclinical studies, the loss of cDC1s resulted in impaired tumor elimination by CD8⁺ T cells and failed response to_ICB therapies^4,8–10. Recent work has identified XCL1 and CCL5 as two key chemokines responsible for recruiting cDC1s into the TME^4,6,11. Given the central role of cDC1s in shaping anti-tumor immunity, harnessing the CCL5-CCR5 and XCL1-XCR1 intercellular signaling axes offers promising therapeutic opportunities to enhance immune responses against cancer.

Chemokines are small (8–12 kDa), secreted proteins best known for their ability to direct cell migration. The chemokine system is comprised of ~50 chemokine ligands that bind and activate ~25 G protein-coupled receptors (GPCR) to induce chemotaxis¹². Based on the number and spacing of conserved cysteine residues, the chemokine family is subdivided into four subfamilies: the CXC, CC, C, and CX3C subfamilies¹². The C-C chemokine ligand 5 (CCL5) belongs to the CC subfamily and binds to the receptor C-C chemokine receptor 5 (CCR5)². In tumors, CCR5 plays an important role recruiting dendritic cells, macrophages, and T cells^4,6,13. The X-C chemokine ligand 1 (XCL1) is unique, in that it is the only member of the C subfamily¹⁴. Unlike most chemokines, it lacks one of the two disulfide bonds required to stabilize the canonical chemokine fold^14,15. As a result, XCL1 spontaneously and reversibly interconverts between two forms – a monomeric, chemokine fold and an alternative dimeric fold. Only the XCL1 chemokine fold binds to and activates X-C chemokine receptor 1 (XCR1) expressed in conventional type 1 dendritic cells (cDC1s), while the XCL1 dimer fold binds to the glycosaminoglycan in the extracellular matrix^14,15. High resolution structure of the Gαi-coupled GPCR XCR1 was recently published¹⁶, illustrating XCL1-XCR1 signaling and function.

During an effective antitumor response, CCL5 and XCL1 are primarily secreted by natural killer (NK) cells to recruit cDC1 to the tumor (Fig. 1)¹⁷. Within the tumor, cDC1s internalize tumor antigen and upregulate the expression of the chemokine receptor CCR7^7,18. Guided by a chemotactic gradient of its cognate ligands CCL19 and CCL21, CCR7 facilitates the migration of activated cDC1s to the tumor-draining lymph nodes, where they prime CD4⁺ T cells and CD8⁺ T cells¹⁷. Intratumoral cDC1s secrete chemokines CXCL9 and CXCL10 that then recruit CXCR3-expressing CD4⁺ T cells and CD8⁺ effector T cells into the tumor, where they initiate cytotoxic killing of the tumor cells^19,20. Meanwhile, intratumoral NK cells secrete the growth factor FMS-like tyrosine kinase 3 ligand (FLT3L), which sustains cDC1 homeostasis and supports local differentiation from its cDC1 precursors^4,20. By secreting interleukin (IL)-12, cDC1s also promote T and NK cells to secrete pro-inflammatory cytokines such as interferon-γ (IFN-γ), thereby amplifying overall anti-tumor immunity. Derailment of any steps of the tumor-lymphatic immune cycle can compromise cDC1 function and hinder successful tumor eradication.

Figure 1. Role of cDC1 in antitumor chemokine signaling.

Conventional type 1 dendritic cells (cDC1s) are recruited into the tumor by chemokines such as XCL1 and CCL5, produced by intratumoral natural killer (NK) cells (and potentially T lymphocytes). Following immunogenic tumor cell death (step 1), cDC1s take up materials from tumor cells and upregulate CCR7. In response to the CCL19/21 gradient, the now CCR7-expressing mature cDC1s transport tumor antigens to tumor-draining lymph nodes, where they prime naïve CD8⁺ T cells into cytotoxic effector CD8⁺ T cells (steps 2,3,4,5). Within lymph nodes (step 5, gray dotted box), DCs provide three critical signals to activate T cells: MHC-peptide-T cell receptor interaction (signal 1, red), costimulation (signal 2, blue), and cytokine secretion (signal 3, purple). Meanwhile, cDC1s in the tumor produce the chemokines CXCL9 and CXCL10, which then recruit CXCR3-expressing Th1 CD4⁺ T cells and CD8⁺ effector T cells into the tumor tissue (steps 6 and 7). In tumors, NK cells secrete the growth factor FLT3L, which supports the survival of cDC1s and might enhance local cDC1 differentiation from DC precursors. Tumor-derived factors such as interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) can hinder the successful recruitment of cDC1s or their differentiation from bone marrow progenitor cells. During an effective immune response, cDC1s secrete IL-12, which, in turn, induces T cells and NK cells within the tumor to secrete more pro-inflammatory cytokines such as interferon-γ (IFN-γ), thereby further boosting the overall anti-tumor immunity. Graphic was adapted from Mellman et al.¹⁷

DC subsets and their functions

While DC ontogeny and differentiation remain an active area of research, the current model posits that very early in hematopoiesis, DC progenitors depart from monocyte/macrophage lineage^21–23. As they exit the bone marrow and enter the peripheral issues, these varied DC progenitor cells undergo two different fates: with the lymphoid-primed multipotent progenitors giving rise to plasmacytoid DCs (pDCs), anti-viral type I interferon (IFN-I)-producing cells²⁴, and the pre-conventional DC1 (pre-cDC1) and pre-conventional DC2 (pre-cDC2) that then diversify into cDC1 and cDC2 (Fig. 1)¹⁷.

In the lymph node, cDC1s can prime CD4⁺ T cells towards a T helper type 1 (Th1) phenotype and launch a Th1 response against intracellular pathogens (e.g. virus) or tumors via the production of interleukin(IL)-2 and the proinflammatory cytokines IFNγ and TNFα^25–27. The cDC2 subset drives the polarization of CD4⁺ T cells into Th17 and Th2 phenotypes, which initiate immune responses (characterized mainly by the production of IL-17 and IL-4/IL-5/IL-13, respectively) against extracellular pathogens, parasites, and allergens^28–33. All cDCs have a short half-life of approximately three to five days in the lymph node and are periodically replenished from bone marrow progenitors in a Flt3L-dependent manner³⁴.

cDC1s depend on the transcription factors BATF3, IRF8, and ID2 for their development, and uniquely express the chemokine receptor XCR1^35–38. Before cDC1s were universally recognized as XCR1⁺ cDC, they were classified as CD8α-type cDCs that excel at tumor antigen cross-presentation or CD103-type migratory cDCs^18,23,39. The two markers are still used to reliably distinguish lymphoid-resident CD8α⁺ cDC1s in mouse tumor-draining lymph nodes (tdLNs) from the CD103⁺ migratory cDC1s that enter the tdLN through afferent lymphatics from tissues or tumors²⁰. Human cDC1s, like murine cDC1s, also selectively express XCR1. The C-type lectin receptor CLEC9A (also known as DNGR-1) and CD141 (BDCA3) are two additional markers commonly used to identify these cells^20,23. It has been shown that CLEC9A binds filamentous actin and allows cDC1 to efficiently capture antigens from dead tumor cells and load them into intracellular vesicles for subsequent processing and delivery to the cell surface for presentation^40,41.

Unlike cDC1s, cDC2s express less specific defining markers, including CD11b and CD172a (SIRPα), which are also detected in monocyte-derived DCs and macrophages^23,42,43. cDC2s are more heterogeneous than previously thought, with varied subsets defined by several surface markers, such as Clec12a, DCIR2, ESAM, or MGL2 (C301b)^29,44,45, as well as the transcription factors T-bet or RORγt⁴⁶. The lack of selective molecular targets to reliably label or ablate cDC2 in tumors makes it challenging to clearly define their contribution to cancer immunity. Nevertheless, it is widely accepted that these cDC2 subsets primarily initiate a CD4⁺ T cell response in anti-cancer immunity^7,35,47,48.

A related DC subset, DC3s, has been identified to share phenotypic features of cDC2, but arises from Ly6C⁺ monocyte-DC progenitors instead of the common DC progenitors that give rise to cDC1s and cDC2s^49,50. In DC-T cell cocultures, Bourdely et al. demonstrated that DC3s can induce differentiation of tissue-resident memory CD8⁺CD103⁺ T cells in vitro⁵⁰. The recent discovery of DC3s as an independent lineage highlights the intricacy and evolving aspects of DC ontogeny as well as ongoing challenges to unanimously define bona fide cDC subsets in inflammatory and tumor settings. Thus, this Review focuses on cDC1s due to their crucial role in anti-tumor immunity, responses to ICB, and well-defined cell surface markers.

Antigen presentation and T cell priming by dendritic cells

Classically, the major histocompatibility complex (MHC) class I pathway is associated with presentation of intracellular antigens such as viral antigens^23,33,51. During an infection, newly synthesized viral proteins are ubiquitinated, cleaved by proteasome, and loaded into MHC class I molecules in the ER lumen, then transported to the Golgi and ultimately to the plasma membrane⁵¹. Alternatively, the MHC class II pathway presents antigens primarily derived from extracellular sources⁵¹. Antigens such as bacteria, protozoans, allergens, or dead cells are internalized by endocytosis into endo-lysosomal compartments where they are subsequently hydrolyzed and proteolytically cleaved into 10–15mer peptides and loaded onto MHC class II molecules for surface presentation⁵¹. Presentation of antigens by cDC2s to their cognate CD4⁺ T cells mostly occurs through the MHC class II complexes^23,33,51. cDC1s, on the other hand, excel at a variation of the MHC class I pathway called cross-presentation⁵¹. In this variation, viral or tumor antigens are internalized via several mechanisms, including endocytosis, phagocytosis, macropinocytosis, and receptor-mediated uptake, before being processed through the vacuolar pathway^52,53. In cancers, infiltrating cDC1s sample tumors via micropinocytosis and phagocytosis, load the acquired tumor antigen onto MHC class I molecules, and cross-present the peptide-MHC class I complexes to their cognate CD8⁺ T cells, thereby initiating effective tumor cell killing^23,33,51,54 (Fig. 1.).

T cell priming occurs primarily within the tdLNs, and is dependent on the trafficking of cDC1s via the chemokines CCL19 and CCL21 and their receptor CCR7 (Fig. 1). Studies using fluorescently labeled tumor cells showed that despite that tumor cDC2s also migrate to the tdLNs, only cDC1s are capable of delivering intact tumor antigens to the tdLN, with the fluorescence predominantly detected in migratory CD103⁺ cDC1 subsets^18,39. Within tdLN, CD103⁺ cDC1s off-load parts of the fluorophore tag to other antigen-presenting cells, including tissue resident CD8α⁺ cDC1s¹⁸. However, migratory CD103⁺ cDC1s, and not tdLN-resident CD8α⁺ cDC1s, are capable of inducing a cancer-specific CD8⁺ T cell response^18,39.

Within lymph nodes, productive T cell priming relies on three critical signals provided by DCs: (1) MHC-peptide-T cell receptor interaction, (2) costimulation, and (3) cytokine secretion⁵⁴ (Fig. 1.). Signal 1, the MHC-peptide-TCR interaction, is stabilized by co-receptors (CD4 or CD8) and serves to ensure that T cells respond to specific pathogens or tumor cells. Signal 2 is sustained by interaction between the costimulatory molecules CD80/86 on DCs and CD28 on T cells, which enhances survival, proliferation, and production of the T cell growth factor IL-2. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint protein that competes with CD28 for the same B7 family molecules (CD80/CD86) found on DCs, which, in turn, dampens T cell activity. Ipilimumab, an anti-CTLA-4 antibody initially approved for the treatment of melanoma^55–57, is now being actively investigated in multiple other cancers. Its clinical importance highlights the DC-T cell immune synapse as a critical druggable target. Conventional CD4⁺ T cells license cDC1s to better prime CD8⁺ T cells via the CD40L-CD40 axis, which upregulates cDC1 expressions of 4–1BBL, CD80/86, and CD70⁵⁸. For signal 3, cytokines such as type I interferons and IL-12 are crucial in creating a pro-inflammatory niche favorable for DC-T cell interactions⁵⁴. These key signals provided by DCs are currently being investigated to optimize priming and generate a robust and durable CD8⁺ T cell-mediated antitumor response.

Limitations in past cancer vaccines and adjuvant therapies

Harnessing DC functions for cancer treatment has been a longstanding concept dating back to the late 1990s^59,60. However, until recently, numerous DC-based therapies fell short of expectation^59–61. These failures occurred, in part, because for many years monocyte-derived DCs (moDCs) were the main DC type generated at large scale in vitro and under clinical best-practice standards for adoptive cell transfer in cancer patients^59–61. But unlike cDC1s and cDC2s, which are the primary DC types residing in secondary lymphoid tissues, moDCs are less competent in trafficking to the lymph nodes and face a greater risk of becoming immunosuppressive rather than immunostimulatory, thus rendering the earlier moDC vaccines ineffective^30,62,63. Recent advances in DC culture and isolation techniques have enabled the successful generation of cDC1s ex vivo at a critical number sufficient to elicit antitumor immunity in vivo^6,64. While the emergence of cDC1-based vaccines is encouraging, several factors including the route of administration (e.g. TME, LN), the antigen load, optimal dosing, and nature of the adjuvant should be carefully considered to produce the desired antitumor response.

Adjuvants commonly used in cancer vaccines include the toll-like receptor (TLR) ligands lipopolysaccharide, polyinosinic:polycytidylic acid, CpG or imiquimod, which are danger signal mimetics that activate DCs⁶⁵. But not all these adjuvants are suitable for human use, and not all TLR agonists are beneficial. For instance, it has been reported that tumor-derived TLR2 ligands generate immunosuppressive IL-10-producing DCs and TLR2 blockade led to improved DC immunogenicity⁶⁶. Anti-CD40 antibodies represent another type of adjuvant that mimics the licensing of DCs by CD4 T cells, allowing the DCs to better prime CD8 T cells. Despite showing preclinical promise, anti-CD40 agonists have not yet attained clinical approval due to their severe side effects including cytokine release syndrome, thrombocytopenia, neutropenia, and multi-organ toxicities^67,68. Similarly, agonists that target the cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS)–stimulator of interferon response cyclic GMP-AMP (cGAMP) interactor 1 (STING) (cGAS-STING) pathway represent another adjuvant strategy that initially received massive enthusiasm for their ability to induce a potent interferon response but faced translational challenges due to their toxicities^69,70. In summary, we still have much to learn about adjuvant cancer therapies to deliver anti-cancer solutions that are safe, efficacious, as well as durable.

Enhancing DC access to the tumor

The absence of cDC1 in tumors is emerging as a key mechanism for cancers to escape immune surveillance. Compared to healthy tissues, cDC1 constitutes less than 5% of leukocytes in mouse and human tumors^39,71,72. Despite their relative scarcity, greater intratumoral cDC1 presence, as determined by flow cytometric analysis and gene transcript levels, correlates positively with survival benefits across multiple cancers^4,71,73. Accordingly, by virtue of their role as cDC1-recruiting chemokines, CCL5 and XCL1 are gaining extensive attention as viable strategies to help cDC1s regain access to the otherwise immune-excluded tumors^4,6,74–76.

In tumors, CCL5 and XCL1 are primarily secreted by NK cells to recruit cDC1s into the tumor, but prostaglandin E2 (PGE₂), a key inflammatory mediator, can directly inhibit this process⁴. By suppressing NK cell viability and their secretion of CCL5/XCL1, PGE₂ impairs cDC1 infiltration². PGE₂ also downregulates expression of CCR5 and XCR1 on cDC1s². PGE₂ is a lipid metabolite of arachidonic acid synthesized by the enzymes cyclooxygenase (COX)1 and COX2^5,77. By genetically ablating the COX1 and COX2 enzymes in tumor cells, Böttcher et al. were able to generate tumors that are PGE₂-deficient and susceptible to cDC1-mediated immune control⁴. In vivo blockade of CCL5 and XCL1 by neutralizing antibodies markedly reduced cDC1 infiltration to the tumor⁴. Conversely, transducing COX-deficient tumors to express CCL5 or XCL1 was sufficient to increase cDC1 accumulation when compared to mock-transduced tumor cells⁴. Following this study in melanoma, Saito et al. similarly induced CCL5 expression in a mouse oral carcinoma (MOC) model and successfully increased the presence of cDC1s in the tumors⁶. Further, they found that only mice bearing CCL5-transduced tumors, but not mice bearing control tumors, restored sensitivity to anti-PD-1 (αPD-1) treatment⁶.

In addition to retrovirally induce CCL5 or XCL1 production in tumors, targeted delivery of cDC1 as a cell-based vaccine or the chemokine XCL1 itself has shown promising results inhibiting tumor growth. For instance, Saito et al. generated a cDC1 vaccine by first isolating cDC1 from the spleen of B16-Flt3L bearing mice, loaded these cDC1 with tumor antigens, and then intratumorally injected the cDC1 vaccine into an αPD-1 resistant tumor⁶. In this study, three consecutive injections of the cDC1 vaccine were sufficient to increase CD8⁺ T cells in the tumor and overcome αPD-1 resistance⁶. Similarly, to study the cDC1-T cell interaction, and more specifically to delineate the XCL1-XCR1 chemokine axis, in our recent study (Ferry et al.¹¹), we transduced tumor-specific P14 T cells (which recognize the LCMV viral gp33 epitope) with XCL1 (CD8^XCL1) or empty vector (CD8^EV) and then adoptively transferred them into B16 melanoma tumor-bearing mice. Compared to mice that received CD8^EV cells, mice that received CD8^XCL1 cells had greater numbers of intratumoral cDC1s and P14 cells, coinciding with delayed tumor growth and survival benefits¹¹. Several groups engineered a highly active XCL1 variant that carries a second disulfide through the introduction of V21C and V59C mutations^74,75,78. Compared to native XCL1, XCL1 V21C/A59C variant demonstrated greater chemotactic activity and suppressed tumor growth to a significantly greater extent⁷⁴.

Challenges and opportunities for DC-based immunotherapy

Besides unsuccessful recruitment of DCs, altered differentiation or decreased survival can also contribute to DC scarcity and dysfunction. For instance, soluble factors such as interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) can suppress differentiation of bone marrow cells into functional mature DCs⁷⁹. Supplementing CCL5 or XCL1 with cytokines such as Flt3L or GM-CSF could help cDC1s to offset these TME immunosuppressive signals. In fact, both Flt3L and GM-CSF are currently being investigated as part of combination therapies with ICB (ClinicalTrials.gov: NCT05029999, NCT04616248, NCT04930783, NCT05760196).

As locally delivered protein ligands, CCL5 or XCL1 may be sensitive to environmental conditions, such as pH and temperature, and consequently, their activity could be short-lived. Nonetheless, direct injection of CCL5 or XCL1 into the target tumor site would allow them to be administered at a high local concentration, which could partially compensate for their initial potential loss. Alternatively, reformulating CCL5 or XCL1 into mRNA-lipid nanoparticles (LNPs)-based vaccines could prolong their expression, while allowing these chemokines to be endogenously translated and stably released from transfected cells⁸⁰ (Fig. 2). Several cytokines, such as IL-12, IL-23, IL-36γ, and OX40L mRNA-LNPs are currently being investigated in the clinic with ICB (ClinicalTrials.gov: NCT03739931, NCT03946800)⁸⁰. Taken together, mRNA-LNPs may represent an efficient drug-delivery system for safe combinatorial use of immune-modulating cytokines, such as Flt3L, with cDC1-recruiting chemokines, such as CCL5 and XCL1, for treating solid tumors.

Figure 2. mRNA-LNP delivery strategies to enhance cDC1-mediated anti-tumor immunity.

As locally delivered protein ligands, CCL5 and XCL1 are potentially subjected to transient activity due to changes in pH and temperature in the tumor microenvironment (TME). The mRNA-lipid nanoparticles (LNPs) delivery system may allow CCL5 or XCL1 to be internalized into target cells, where they can be stably synthesized and then released into the TME. Supplementing cDC1-recruitment chemokines with cytokines, such as Flt3L or GM-CSF, could further support cDC1 maturation, abundance, and immune functions, thereby amplifying overall anti-tumor immunity.

Conclusion and future perspectives

In the context of tumor immunity, cDC1s are arguably the best characterized DC subsets compared to their other DC counterparts. An added layer of complexity to DC biology is the varied functional states in which they can exist during inflammation. Relevant transcriptional DC states described to date include (i) CCR7⁺ DCs, which are dominant DC population that migrate to tumor draining lymph node⁸¹; (ii) mregDCs, which are mature DCs enriched in immunoregulatory molecules and drive the differentiation of Tregs⁸²; and (iii) interferon-stimulated genes (ISG)⁺ DCs⁸², which are stimulated cDC2s capable of acquiring tumor antigens and activate CD8⁺ T cells⁸³. Considering these various DC actors and their specific division of labor at play, our understanding of the complex DC network remains fragmentary and largely dependent on specific tumor and inflammatory contexts that warrant further investigation.

A critical part of the DC-mediated anti-tumor immunity is the chemokine-chemokine receptor signaling networks. Except for the XCL1-XCR1 and CXCL9/10-CXCR3 axes, which are widely accepted to be anti-tumorigenic⁸⁴, the ability to exploit other chemokine-receptor systems to increase the anti-tumor response, including the CCL5-CCR5 axis, is less clear. For instance, there have been reports of the CCL5-CCR5 axis recruiting both anti-tumorigenic immune cells (e.g. NK cells, CD8⁺ T cells, and cDC1s)^5,6 and pro-tumorigenic immune cells (e.g. myeloid-derived suppressor cells, and regulatory T cells)^85,86. The resulting immune response likely depends on the overall context of the TME, which can be shaped by various factors. These include the stage of tumorigenesis, the state of immune cell activation, the balance between effector and regulatory responses, and the relative expression of chemokine ligands and receptors. Among the varied chemokine permutations, the XCL1-XCR1 axis emerges as a cell-type-specific and compelling strategy to be explored for overcoming ICB resistance.

As ICB cancer immunotherapy transitions into the adjuvant, neoadjuvant, and perioperative settings, a combinatorial approach of vaccination with cDC1-supporting cytokines, chemokines, and ICB therapies likely is needed to maximize productive T cell priming and anti-tumor response. In this review, we highlight the CCL5-CCR5 and XCL1-XCR1 axes as two chemokine signaling networks involved in enhancing cDC1 entry into the otherwise immune-cold tumor. Besides facilitating immune cell migration, it remains unclear whether the CCL5-CCR5 and XCL1-XCR1 signaling axes also orchestrate the positioning, retention, survival, proliferation, and differentiation of DCs and their interacting cell partners, which remains an area of active investigation. Future research exploring these key biological questions will help inform the rational design of next-generation DC vaccine and chemokine-based immunotherapies, thereby enhancing the response to ICB and achieving complete and durable tumor regression.

Significance Statement.

The lack of cDC1s in tumors represents a major roadblock for current cancer immunotherapies. Here, we highlight two chemokines, CCL5 and XCL1, that are critical for recruiting cDC1s to the tumor microenvironment where they uptake tumor antigens and cross-present antigens to T cells following migration to the lymph nodes. We further discuss recent advances and limitations in current dendritic cell (DC) vaccine design and cancer adjuvant therapies and propose new strategies to enhance cDC1 recruitment into tumors.

Abbreviations:

DC

dendritic cell

cDC1

conventional type 1 dendritic cell

cDC2

conventional type 2 dendritic cell

ICB

immune checkpoint blockade

αPD-1

anti-PD-1

tdLN

tumor-draining lymph node

TME

tumor microenvironment

XCL1

X-C chemokine ligand 1

XCR1

X-C chemokine receptor 1

CCL5

C-C chemokine ligand 5

CCR5

C-C chemokine receptor 5