Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity

Abstract

Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.

Keywords: Th1; Th17; Th2; chemokine; chemokine receptor; dendritic cell; macrophage; neutrophil; regulatory T; tumor microenvironment.

Figure 1

Chemokine-mediated T cell immune responses in the lymph node. In primary immune responses, antigen-captured DCs migrate into the draining lymph nodes via afferent lymphatics using the CCL19/CCL21-CCR7 axis. In the lymph nodes, mature DCs produce CCL19 and interact with recirculating CCR7-expressing naïve CD4⁺ T cells that home into the lymph nodes via the high endothelial venules (HEVs). If stimulated by cognate antigenic peptides presented by mature DCs, naïve T cells differentiate into Th1 cells, Th2 cells, Th17 cells, and Treg cells according to the local cytokine milieu.

Figure 2

Roles of Th17 cells in tumor immunity. Th17 cells have both pro-tumor and anti-tumor activities in tumor immunity. IL-17A induces the production of angiogenic factors such as VEGF, PGE2, CXCL1, and NO from tumor cells and fibroblasts, leading to increase in angiogenesis. IL-17A also enhances the infiltration of MDSCs into tumor tissues. On the other hand, Th17 cells can directly induce tumor-specific CTLs via IL-2 production and MHC class I molecule expression in the lymph node. IL-17A also induces NK cells to express natural cytotoxicity receptor, perforin, TNF, and IFN-γ, and macrophages to express IL-1, IL-6, IL-12, and TNF. Furthermore, IL-17A induces the production of CXCL9 and CXCL10 in tumor cells and CCL20 in macrophages. These chemokines recruit CXCR3-expressing CTLs and CCR6-expressing immature DCs, respectively. In addition, IL-17F, IL-21, and IL-22 inhibit angiogenesis.

Figure 3

Roles of Treg cells in tumor immunity. In the tumor microenvironment, TAMs, TANs, tumor cells, and cancer-associated fibroblasts secrete CCL17 and/or CCL22, and recruit CCR4-expressing Treg cells into tumor tissues. Infiltrated Treg cells secret immunosuppressive cytokines such as IL-10, TGF-β, and IL-35. These cytokines suppress the activation and induction of tumor-specific T cell responses and induce T cell exhaustion. TGF-β also enhances the differentiation and immunosuppressive function of MDSCs. Furthermore, adenosine is generated from ATP derived from apoptotic Treg cells and inhibits the function and proliferation of effector T cells. Treg cells also inhibit the costimulatory signals of DCs to induce tumor-specific T cell responses by the CTLA-4-CD80/CD86 interaction.