Impact of antiangiogenic treatments on exhausted PD-1+ T lymphocytes in colorectal cancer.

e22121 Background: Tumors develop immunosuppressive mechanisms to escape the immune system. Among these mechanisms, T lymphocytes can express inhibitory molecules such as Program Death-1 (PD-1) protein which impair their activation and their effector functions. 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 modulate immunosuppressive mechanisms especially regulatory T cells. However, the role of specific VEGF/VEGFR blockade on PD-1 expression by T lymphocytes has not been studied. Methods: PD-1 expression on T lymphocytes has been analyzed by flow cytometry in a mouse model of colorectal cancer (CT26) treated by anti-angiogenic molecules targeting the VEGF-A/VEGFR axis and in the peripheral blood of metastatic colorectal cancer patients. Results: Sunitinib that directly targets VEGFR, PDGFR, c-kit, but also anti-VEGF-A antibody (the mouse orthologue of bevacizumab) decrease PD-1 expression on T lymphocytes infiltrating the tumors. Interestingly, anti-angiogenic treatments decrease the percentage of lymphocytes expressing not only PD-1 but also Tim-3 suggesting that the most exhausted T cells are targeted by anti-angiogenic treatments. Administration of masitinib, a TKI acting on KIT, PDGFR and FAK but not on the VEGF/VEGF-R pathway, was not able to modulate PD-1 expression on T cells. Finally, anti-VEGF-A treatment (bevacizumab) associated with chemotherapy decreases the proportion of PD-1+ CD4+T cells in the peripheral blood of metastatic colorectal cancer patients. Conclusions: These results show that anti-angiogenic treatments targeting VEGFA/VEGFR decrease PD-1-expressing T lymphocytes in colorectal cancer. These results suggest that VEGF-A could be involved in PD-1 expression and maybe in the induction of T lymphocyte exhaustion in colorectal cancer. We and others have shown that anti-angiogenic molecules could modulate other immunosuppressive populations such as regulatory T cells and myeloid suppressive cells, anti-angiogenic molecules might be efficiently associated with immunotherapeutic strategies in colorectal cancer.