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

Abstract

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.

Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy

“…In vitro and in vivo studies have further revealed that these anticancer effects of ARB include direct suppression of cancer growth and increase of antitumor immunity [ 35 – 38 ]. Nakamura et al showed that administration of ARB to colon cancer-bearing mice induced the expansion of cancer-specific CTLs and reduced the levels of immune-suppressive cytokines, interleukin-6 (IL-6), IL-10, vascular endothelial cell factor, and arginase in the tumor microenvironment [ 39 ]. They demonstrated that combination therapy with ARB and anti PD-L1 antibody significantly reduced tumor size, suggesting that this therapy is also useful in clinical setting.…”

Colon-specific immune microenvironment regulates cancer progression versus rejection

“…Most preclinical mouse models investigating the immune composition of CRC tumors are based on the implantation of colon tumor cell lines under the skin [35,36]. Nevertheless, our past work has revealed that the skin microenvironment does not accurately reproduce the microenvironment of organs from which tumor cells originate [9].…”

Expression of the Components of the Renin-Angiotensin System in Oncological Diseases

“…On the other hand, Shen J. et al, 2016). It is shown that microenvironment tumor cells from mice immunized colon cancer cells, by promoting the escape of anticancer immunity, formed by macrophages and cancer-associated fibroblasts (Nakamura K. et al, 2018). According to the authors, a sharp increase in the level of expression of ACE macrophages may indicate to increase local production of the intensity of immunosuppressive molecules, such as nitric oxide, TGF-b1, PGE2.…”