Osteopontin controls immunosuppression in the tumor microenvironment

Abstract

Cancer cells evade the immune system through a variety of different mechanisms, including the inhibition of antitumor effector T cells via checkpoint ligand-receptor interaction. Moreover, studies have shown that blocking these checkpoint pathways can reinvigorate the antitumor immunity, thereby prompting the development of numerous checkpoint immunotherapies, several of which are now being approved to treat multiple types of cancer. However, only a fraction of patients achieves promising long-term outcomes in response to checkpoint inhibition, suggesting the existence of additional unknown tumor-induced immunosuppressive pathways. In this issue of the JCI, Klement and colleagues describe an additional pathway of T cell inhibition in cancer. Specifically, the authors demonstrate that downregulation of IRF8, a molecular determinant of apoptotic resistance, in tumor cells aborts repression of osteopontin, which in turn binds to its physiological receptor CD44 on activated T cells and suppresses their activation. These results suggest that osteopontin may act as another immune checkpoint and may serve as a target to expand the number of patients who respond to immune checkpoint inhibitor therapy.

Figure 1. IRF8-controlled expression of osteopontin in the tumor microenvironment suppresses activity of T cells and supports tumor progression.

Osteopontin (OPN) has diverse biological functions in many physiological and pathological processes. Via its cytokine, chemotactic, and cell signaling functions, OPN regulates inflammation, biomineralization, tissue remodeling, and angiogenesis. In the tumor microenvironment, OPN facilitates cell-matrix interactions and promotes tumor progression. In this issue of the JCI, Klement et al. demonstrate that OPN may also suppress activity of cytotoxic CD8⁺ T lymphocytes (CTLs), thereby contributing to progression of malignant disease. OPN is highly expressed in myeloid regulatory cells (MRCs) and malignant cells, two major components of the tumor microenvironment, and suppresses T cell proliferation and IFN-γ secretion by binding to CD44, which is highly expressed on activated T lymphocytes. IRF8 may act as a tumor suppressor, as it represses OPN (encoded by SPP1) expression in normal epithelial cells. Nevertheless, IRF8 expression is silenced and OPN expression is elevated during transformation of epithelial cells into a malignant phenotype. Together, this suggests that tumor cells and myeloid regulatory cells may exploit downregulation of IRF8 to upregulate OPN as a mechanism to suppress CD8⁺ T cell–mediated antitumor immunity.