174O - VEGF-a-induced Treg Proliferation, A Novel Mechanism of Tumor Immune Escape in Colorectal Cancer: Effects of Anti-VEGF/VEGFR Therapies

Abstract

ABSTRACT Background Regulatory T cells (Treg) are suspected of hindering an effective antitumor immune response in cancer. Multi-target anti-angiogenic tyrosine kinase inhibitors (TKI) that are routinely used as first or second line treatment of cancer patients, have been shown to decrease Treg proportion in tumor-bearing mice and metastatic renal cancer patients. However, the role of VEGF/VEGFR blockade in this effect is still debatable, and the direct impact of VEGF-A on Treg has not been studied. Methods Treg proportion, number were analyzed by flow cytometry in peripheral blood of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, and in CT26 tumor-bearing mice treated with drugs targeting the VEGF axis. The direct impact of VEGF on Treg increase in cancer was also studied. Results Sunitinib (a TKI targeting VEGFR, PDGFR, c-kit), and anti-VEGF-A antibody both decreased Treg in CT26 tumor-bearing mice. Masitinib, a TKI that does not target VEGFR, did not reduce Treg proportion in CT26 bearing mice. Bevacizumab, an anti-VEGF-A monoclonal antibody, reduced Treg proportion in peripheral blood of mCRC patients. Proliferation of Treg was enhanced in CT26 tumor-bearing mice compared to tumor-free mice and was decreased after anti-VEGF-A treatment. Furthermore, in vitro experiments have shown that VEGF-A could directly induce Treg proliferation. VEGFR1 and 2 were expressed on Treg in the presence of a tumor. Anti-VEGFR2 antibody administration reduces Treg proportion and also proliferation in CT26 bearing mice, but anti-VEGFR1 antibody did not, suggesting that VEGF-A-induced Treg proliferation was dependent on VEGFR2 expression. In metastatic CRC patients, Treg proliferation was also enhanced compared to healthy volunteers and was blocked by bevacizumab treatment. Conclusions We identified a new mechanism by which VEGF-A induced by the tumor could stimulate Treg proliferation. VEGF-A/VEGFR2 blockade reduced Treg proportion and proliferation in tumor-bearing mice and metastatic CRC patients suggesting that combination of anti-VEGF-A/VEGFR2 therapies with immunotherapeutic approaches in the future might be particularly relevant in CRC patients. Disclosure J. Taieb: advisory role, Roche; research grant, Roche. All other authors have declared no conflicts of interest.