Involvement of local renin–angiotensin system in immunosuppression of tumor microenvironment

Abstract

To improve the current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSCs) which were shown to be negative factors in the immune-checkpoint blockade therapy, need to be developed. In this study, we have evaluated the role of local renin–angiotensin system (RAS) in the tumor immune-microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Administration of angiotensin II receptor blockers (ARBs) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b⁺ myeloid cells in tumors, but significantly reduced their T cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, VEGF, and arginase by CD11b⁺ cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer-associated fibroblasts (CAFs). Lastly, combination of ARB and anti-programmed death-ligand 1 (PD-L1) antibodies resulted in significant augmentation of anti-tumor effects in a CD8⁺ T cell-dependent manner. These results demonstrated that RAS is involved in generation of immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSCs and CAFs and could be used in combination with PD-1/PD-L1 immune checkpoint blockade therapy.

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