Chemokines in cancer

Abstract

Chemokines are chemotactic cytokines that control the migration of cells between tissues and the positioning and interactions of cells within tissue. The chemokine superfamily consists of approximately 50 endogenous chemokine ligands and 20 G protein-coupled seven-transmembrane spanning signaling receptors. Chemokines mediate the host response to cancer by directing the trafficking of leukocytes into the tumor microenvironment. This migratory response is complex and consists of diverse leukocyte subsets with both antitumor and protumor activities. Although chemokines were initially appreciated as important mediators of immune cell migration, we now know that they also play important roles in the biology of nonimmune cells important for tumor growth and progression. Chemokines can directly modulate the growth of tumors by inducing the proliferation of cancer cells and preventing their apoptosis. They also direct tumor cell movement required for metastasis. Chemokines can also indirectly modulate tumor growth through their effects on tumor stromal cells and by inducing the release of growth and angiogenic factors from cells in the tumor microenvironment. In this Masters of Immunology primer, we focus on recent advances in understanding the complex nature of the chemokine system in tumor biology with a focus on how the chemokine system could be used to augment cancer immunotherapeutic strategies to elicit a more robust and long-lasting host antitumor immune response.

Figure 1. Multifaceted roles of chemokines in tumor development

(1) Chemokines produced by tumor cells, intratumor stromal cells, such as fibroblasts, and intratumor leukocytes can attract different immune cell types into the tumor bed. The composition of immune cells in the tumor can affect the outcome of development. (2) Tumor- and stromal cell-derived chemokines can directly support the growth, proliferation and survival of tumor cells. (3) Chemokines released by tumor cells, stromal cells and leukocytes can regulate the process of angiogenesis by their angiogenic or angiostatic activity. (4) Chemokines produced within the tumor can induce the release of tumor-promoting growth factors that can act in a paracrine fashion to promote tumor growth. (5) Chemokines are also involved in the migration of tumor cells to distant sites for the development of metastasis. CD8 T – CD8⁺ T cell; Th1 – Th1-type CD4⁺ T cells; NK – natural killer cell; Treg – regulatory T cell; MDSC – myeloid-derived suppressor cell; TAM – tumor–associated macrophage.