Journal Article

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

Okuyama, Ryuhei, Kobayashi, Asuka, Yaguchi, Tomonori, Kawakami, Yutaka, Ohmura, Gaku, Kawamura, Naoshi, Iwata, Takashi, Nakamura, Kenta, Kiniwa, Yukiko

2018

Overview

To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune‐checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the 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. Giving angiotensin II receptor blockers (ARB) 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, vascular endothelial growth factor (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 (CAF). Last, 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 way. These results showed that RAS is involved in the generation of an 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 MDSC and CAF and could be used in combination with PD‐1/PD‐L1 immune‐checkpoint blockade therapy. Local renin–angiotensin system is involved in generation of immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts. Angiotensin receptor blockers can transform the immunosuppressive properties of myeloid derived suppressor cells and cancer‐associated fibroblasts and could be used in combination with PD‐1/PD‐L1 immune checkpoint blockade therapy.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Angiogenesis / Angiotensin / Angiotensin II / angiotensin receptor antagonist / Angiotensin Receptor Antagonists - administration & dosage / Angiotensin Receptor Antagonists - pharmacology / Animal models / Animals / Antigens / Antigens, Neoplasm - immunology / Apoptosis / Arginase / Cancer immunotherapy / Cancer therapies / Cancer-Associated Fibroblasts - drug effects / Cancer-Associated Fibroblasts - immunology / cancer‐associated fibroblast / CD11b antigen / CD8 antigen / Cell culture / Cell growth / Cell Line, Tumor / Chemokines / Chemotherapy / Colon cancer / Colonic Neoplasms - drug therapy / Colonic Neoplasms - immunology / Colonic Neoplasms - metabolism / Cytokines / Fibroblasts / Humans / Immune checkpoint / Immunosuppression / Immunotherapy / Ligands / Lymphocytes T / Macrophages / Medical research / Mice / Mice, Inbred C57BL / myeloid cell / Myeloid cells / Neoplasm Transplantation / Nitric Oxide / Nitric-oxide synthase / Original / PD-L1 protein / programmed cell death 1 receptor / Renin / Renin-Angiotensin System - drug effects / renin‐angiotensin system / Studies / Suppressor cells / Tumor cell lines / Tumor Microenvironment - drug effects / Tumors / Vascular endothelial growth factor