Abstract 373: Impact of anti-angiogenic treatments on exhausted PD-1+ T lymphocytes in colorectal cancer.
Authors: Terme Magali , Voron Thibault , Marcheteau Elie , Colussi Orianne , Pernot Simon , Tartour Eric , Taieb Julien 
Published: August 2014

Abstract
Background: The concept of cancer immunosurveillance suggests that the immune system can recognize and destroy tumor cells. However, tumors can develop immunosuppressive mechanisms to escape the immune system. Among the immunosuppressive mechanisms, T lymphocytes can express inhibitory molecules such as Program Death-1 (PD-1) protein which impair their activation. PD-1 activation by its ligands PD-L1 and PD-L2 blocks T cell proliferation, cytolytic activity, cytokine production, and decreases survival. 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.
Materiel and 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: Tumor-infiltrating CD4+ and CD8+ T lymphocytes express high levels of PD-1 in the CT26 tumor model. Sunitinib that directly targets VEGFR, PDGFR, c-kit, decreases PD-1 expression on CD4+ and CD8+ T lymphocytes infiltrating the tumors. In the same manner, anti-VEGF-A antibody (the mouse orthologue of bevacizumab) restrains PD-1 expression on tumor-infiltrating T lymphocytes. 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 tyrosine kinase inhibitor 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. This point is currently under investigation. 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.
Citation Format: Magali Terme, Thibault Voron, Elie Marcheteau, Orianne Colussi, Simon Pernot, Eric Tartour, Julien Taieb. Impact of anti-angiogenic treatments on exhausted PD-1+ T lymphocytes in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 373. doi:10.1158/1538-7445.AM2013-373