Abstract 3238: SIRPa blockade reinvigorates myeloid cells in the tumor microenvironment and reverses T-cell exclusion

Abstract

Cancer immunotherapies by immune checkpoint blockade (CKI) has shown great therapeutic efficacy by helping the immune system to recognize and attack cancer cells. However, a significant percentage of patients do not respond or develop resistance. T-cell exclusion from tumor core, mediated by myeloid cells and fibroblast colonizing the tumor micro-environment, has been described as an important factor of resistance to checkpoint inhibitors. Myeloid cells represent one of the most abundant immune cell types in many solid tumors and are often associated with a poor outcome. Interaction of SIRPalpha (SIRPa), expressed by myeloid cells, with the ubiquitous receptor CD47 is an important immune checkpoint of the innate response, involved in the regulation of macrophages and dendritic cells functions (e.g. phagocytosis, antigen presentation). Here we evaluated the impact of selective SIRPa blockade on the function of myeloid cells from tumor micro-environment. In vivo , in an orthotopic and syngeneic hepatocellular carcinoma (HCC) mouse model, anti-SIRPa antagonist monoclonal antibody in combination with an adaptive immune checkpoint inhibitor (anti-PD-L1) dramatically enhanced overall survival and lead to complete remission in up to 60% of immunocompetent mice (p In vitro , we next observed that CD47-induced signals inhibited secretion of chemokines by immature human macrophages. This inhibition could be reversed by a selective anti-SIRPa antagonist mAb. Ex-vivo , selective anti- SIRPa antagonist mAbs significantly increased the chemokine transcriptomic expression signature of human myeloid cells purified from ovarian cancer ascites or of HCC tumor explant fragment maintained in culture for 48 hours. Finally, we found in vivo in a humanized mice model of transmigration that SIRPa blockade significantly increased human T cell migration in microenvironment locally enriched by human macrophages. In conclusion, we showed that selective SIRPa antagonist mAbs synergized with T-cell CKI by modifying the tumor microenvironment, in particular the chemokine secretion by mouse or human myeloid cells which contributes to limit T cell exclusion and favors efficient and robust anti-tumor immune responses. Citation Format: Vanessa Gauttier, Sabrina Pengam, Justine Durand, Kevin Biteau, Melanie Neel, Sophie Conchon, Dominique Costantini, Bernard Vanhove, Nicolas Poirier. SIRPa blockade reinvigorates myeloid cells in the tumor microenvironment and reverses T-cell exclusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3238.