Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

Abstract

The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer.

Figure 1. Chemokine receptor and ligand pairings

The chemokine receptors and ligands that belong to each of the main chemokine families (namely, the C-, CC-, CXC- and CX₃C-chemokine families) are shown. Blue and red boxes represent chemokine–chemokine receptor interactions that occur in mice and humans, respectively, and the non-boxed interactions occur in both humans and mice. Abbreviations enclosed in parentheses indicate alternative names for the preceding chemokine or chemokine receptor. Question marks indicate that the respective chemokine receptor is currently unknown.

Figure 2. The promotion of tumour immunity by chemokines

Immune cells with antitumour effects — such as CD8⁺ T cells, T helper 1 (T_H1) cells, polyfunctional T_H17 cells and natural killer (NK) cells — are recruited to the tumour microenvironment through chemokine–chemokine receptor signalling pathways. CXC-chemokine receptor 3 (CXCR3) and its ligands CXC-chemokine ligand 9 (CXCL9) and CXCL10 have a key role in driving the trafficking of T_H1 cells, CD8⁺ T cells and NK cells into the tumour microenvironment, whereas CC-chemokine ligand 20 (CCL20) signalling through CC-chemokine receptor 6 (CCR6) promotes the recruitment of T_H17 cells. Antigen-presenting cells (APCs) such as macrophages and dendritic cells are also recruited into the tumour microenvironment, and they can activate and expand the local effector immune cells, thereby promoting tumour regression.

Figure 3. Pro-tumour effects of chemokines

Immune cell populations such as granulocytic and monocytic myeloid-derived suppressor cells (MDSCs), regulatory T (T_reg) cells, IL-22⁺CD4⁺ T helper 22 (T_H22) cells, IL-22⁺ innate lymphoid cells (ILCs) and plasmacytoid dendritic cells (pDCs) can promote tumour growth. These cells are recruited to the tumour microenvironment in response to different chemokines that are expressed in the tumour microenvironment (the relevant receptors and ligands are shown). Pro-tumour immune cells may inhibit antitumour immune responses, and may also promote and maintain cancer stemness and angiogenesis, leading to cancer progression. CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; CXCL, CXC-chemokine ligand; CXCR, CXC-chemokine receptor.

Figure 4. The relationship between, and mechanisms that underlie, tumour immune phenotype and biological phenotype

Active tumour β-catenin signalling inhibits CC-chemokine ligand 4 (CCL4) expression, and limits CD103⁺ dendritic cell (DC) recruitment and CD8⁺ T cell activation and expansion. The expression of the genes encoding the T helper 1 (T_H1)-type chemokines CXC-chemokine ligand 9 (CXCL9) and CXCL10 is repressed by the histone-lysine N-methyltransferase enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase (DNMT)-mediated epigenetic silencing. Consequently, CD8⁺ T cells poorly infiltrate the tumour, and the tumour is immunologically ‘cold’ (left). High levels of tumour β-catenin, EZH2 and DNMTs endow cancer stemness, which can be further promoted and maintained by pro-tumour immune cells. Thus, the immunologically cold tumour is biologically prone to have a more stem-like phenotype. Reversing this mechanism by epigenetic reprogramming and the suppression of β-catenin signalling may make the tumour immunologically ‘hot’ and promote the recruitment of effector immune cells with antitumour functions (including T_H1 cells, natural killer (NK) cells, CD8⁺ T cells, polyfunctional T_H17 cells and functional antigen-presenting cells (APCs)), thereby driving tumour regression. MDSC, myeloid-derived suppressor cell; PDL1, programmed cell death protein 1 ligand 1; T_reg cell, regulatory T cell.