Abstract A72: IFNAR1 signaling regulates PMN-MDSCs immune suppressive activity in cancer

Polymorphnuclear myeloid-derived suppressor cells (PMN-MDSCs) are a subset of MDSCs that are expanded and accumulated in several cancers. The main role of PMN-MDSCs in cancer is the suppression of antitumor immune responses, which leads to tumor progression, angiogenesis and metastasis. PMN-MDSCs within the tumor microenvironment (TME) have potent immune-suppressive effects compared to PMN-MDSCs in peripheral organs. However, the mechanism regulating the immune-suppressive activity of PMN-MDSCs within the TME remain poorly understood. Recently, it was shown that PMN-MDSCs from spleen of tumor-bearing mice treated with type 1 interferon (IFN1) have a decrease in their immune-suppressive activity. It has been established that tumor-associated PMN-MDSCs are more suppressive than those residing in the spleen; however, their response to IFN1 remains unclear. Therefore, our goal is to understand the role of IFN1 in the regulation of PMN-MDSCs’ function within the TME. We found that IFN1 receptor, IFNAR1, is downregulated in tumor-associated PMN-MDSCs compared to their counterparts in the spleen. In cancer patients IFNAR1 on PMN-MDSC was substantially lower than on neutrophils from healthy donors. IFNAR1 downregulation in PMN-MDSCs correlated with their immune-suppressive activity. To understand the importance of IFNAR1 signaling in PMN-MDSC biology, we utilized a knock-in mouse expressing a mutant form of IFNAR1 (Ifnar1SA) that is resistant to downregulation upon stimuli and stress. PMN-MDSCs from Ifnar1SA mice were defective in their immune-suppressive activity whereas PMN-MDSCs from Ifnar1-/- mice are as immunosuppressive as PMN-MDSCs from WT mice. In this study, we described the possible role of IFN1 in negative regulation of PMN-MDSCs function in cancer. Citation Format: Serge Fuchs, Kevin M. Alicea-Torres, Dmitry I. Gabrilovich. IFNAR1 signaling regulates PMN-MDSCs immune suppressive activity in cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A72.