Physiology of chemokines in the cancer microenvironment

Abstract

Chemokines are chemotactic cytokines whose canonical functions govern movement of receptor-expressing cells along chemical gradients. Chemokines are a physiological system that is finely tuned by ligand and receptor expression, ligand or receptor oligomerization, redundancy, expression of atypical receptors, and non-GPCR binding partners that cumulatively influence discrete pharmacological signaling responses and cellular functions. In cancer, chemokines play paradoxical roles in both the directed emigration of metastatic, receptor-expressing cancer cells out of the tumor as well as immigration of tumor-infiltrating immune cells that culminate in a tumor-unique immune microenvironment. In the age of precision oncology, strategies to effectively harness the power of immunotherapy requires consideration of chemokine gradients within the unique spatial topography and temporal influences with heterogeneous tumors. In this article, we review current literature on the diversity of chemokine ligands and their cellular receptors that detect and process chemotactic gradients and illustrate how differences between ligand recognition and receptor activation influence the signaling machinery that drives cellular movement into and out of the tumor microenvironment. Facets of chemokine physiology across discrete cancer immune phenotypes are contrasted to existing chemokine-centered therapies in cancer.

Keywords: cell migration; chemokine receptor; immuno-oncology; metastasis; tumorigenesis.

Graphical abstract

Figure 1.

Chemokine functions in leukocyte circulation and extravasation. Tissue injury or infection with microbial agents stimulate the production of chemokines in discrete epithelial cells, endothelial cells, and fibroblasts in peripheral tissues and organs. Glycosaminoglycans play an important role in sculpting and enforcing the formation of chemokine gradients needed for leukocyte extravasation and migration into tissues. The highly sulfated and acidic residues present on glycosaminoglycans bind negative residues on chemokines, creating localized concentrations of chemokines in discrete endothelial and tissue locations. Glycosaminoglycans may also influence oligomerization of chemokine ligands. Immune cells follow the chemical gradient, moving from areas of low concentration to higher levels of ligand.

Figure 2.

Signaling of chemokine-activated receptors. Chemokine receptors and ligands can either be balanced (green circles and shading), G-protein biased (blue circles and shading), or β-arrestin biased (red circles and yellow shading). Figure created with BioRender.com.

Figure 3.

Overview of chemokine physiology. A: the conventional wisdom is that chemokines function as single ligands binding to a cognate receptor and inducing chemotactic migration from least to highest ligand expression. This unidirectional functional model of chemokine function can be depicted as a two-dimensional barcode where migration reflects ligand recognition by its receptor. B: chemokine physiology increasingly recognizes multiparametric pharmacological and cellular variables impacting both ligand and receptor, suggesting functional outcomes require an integrated multidimensional QR-code-type interpretation of these varying inputs. B, top: variables include migration as a biphasic curve with little cell movement at the lowest and highest concentrations of ligand, the formation of homo- or hetero-oligomers, binding to nonreceptor glycosaminoglycans or amino-terminal proteolytic cleavage. B, bottom: variables include biased signaling through the G-protein-coupled receptors, homologous or heterologous receptor desensitization, activation of discrete signaling pathways, and “traditional” or “atypical” chemokine receptors that mediate calcium signaling or ligand internalization, respectively. Figure created with BioRender.com.

Figure 4.

Chemokines in cancer immunophenotype. The cancer immune microenvironment has been broadly classified into immune-inflamed, immune-excluded, or immune-desert subtypes. The immune-inflamed microenvironment is characterized by populations of effector T cells, conventional dendritic cells, and inflammatory-type tumor-associated macrophages. Tumors with an immune desert-type environment are predominated by fewer effector T cells and a preponderance of wound repair-type tumor-associated macrophages and regulator T cells. Immune-excluded tumor microenvironments have fewer immune cells in close proximity with cancer cells and may have elevated levels of stromal cells and tumor-associated neutrophils. Figure created with BioRender.com.

Figure 5.

Two illustrative examples of chemokine-biased signaling. A: CCL19, CCL21, and CCR7 exhibit cell (or tissue) bias. CCL19 at low concentrations maintains migration of CCR7-expressing dendritic cells into draining lymph node. Although both bind CCR7 with comparable efficacy, CCL21 chemoattracts T cells with less potency than CCL19. CCL21 also exhibits a greater ability to bind glycosaminoglycans found in high endothelial venules compared with CCL19. B: optimal concentrations of the chemokine CXCL12 stimulate chemotaxis and balanced agonist signaling through its cognate receptor CXCR4. At this narrow concentration, CXCL12 primarily maintains a monomer configuration. As CXCL12 concentrations increase, or in the presence of receptor or GAG-binding partners, CXCL12 dimerization is enhanced. Dimerized CXCL12 binding to CXCR4 activates a G-protein-biased signaling pathway that inhibits cell movement. Figure created with BioRender.com. GAGs, glycosaminoglycans.