Autocrine PGE2 signaling shapes the immune suppressive states of Tumor-Associated Neutrophils 2991

Abstract Description The highly heterogeneous and plastic nature of tumor-associated neutrophils (TANs) in various solid tumors is well recognized. Although recent studies have revealed that effective tumor control induced by immunotherapy is linked to a robust neutrophil response characterized by interferon gene signatures, majority of TANs are believed to be immune suppressive when infiltrating solid tumor. How do TANs overcome the reprogramming effects from immunotherapy and maintain their immune suppressive cell states remain unclear. Here, we unveiled a critical role of autocrine PGE2 signaling in maintaining the immune suppressive cells states. Mechanistically, we have found that the PGE2 signaling can disrupt the interferon responses in TANs, thus, preventing the TANs from being reprogrammed by IFNγ during the immunotherapy treatment. Importantly, we also identified a subset of Sox2Hi tumor-initiating stem cells (tSCs) located at the tumor-stroma interface that can upregulate Fatty Acid Desaturase 1 (Fads1) to produce arachidonic acid. This tSC-specific pathway promotes autocrine PGE2 signaling in TANs, thereby orchestrating the immune suppressive states of TANs. These findings highlight a previously unrecognized mechanism by which tSCs can modulate the autocrine PGE2 signaling of TANs to subvert antitumor responses, providing new insights into potential therapeutic interventions to normalize the myeloid cell-mediated tumor microenvironment and enhance the efficacy of immunotherapy. Funding Sources NIH R01CA285786 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)