Platelet-activating factor (PAF) promotes immunosuppressive neutrophil differentiation within tumors 2759

Description Chronic inflammatory milieu in the tumor microenvironment (TME) leads to the differentiation of myeloid-derived suppressor cells (MDSCs). Polymorphonuclear (PMN)-MDSCs, which are phenotypically and morphologically defined as a subset of neutrophils, cause major immune suppression in the TME, posing a significant challenge in the development of effective immunotherapies. Despite recent advances in our understanding of PMN-MDSC functions, the mechanism that gives rise to immunosuppressive neutrophils within the TME remains elusive. We discovered that newly recruited neutrophils into the tumor sites remained activated and highly motile for more than five days and developed immunosuppressive phenotypes by suppressing anti-cancer CD8 T cell cytotoxicity. The strong suppressive function was successfully recapitulated by incubating naïve neutrophils with cancer cell culture supernatant in vitro. Cancer metabolite secretome analyses of the culture supernatant revealed that both murine and human cancers released lipid mediators to induce the differentiation of immunosuppressive neutrophils. Mass spectrometry lipidomic analysis identified platelet activation factor (PAF) as a common tumor-derived lipid mediator that induces MDSC differentiation. LPCAT2, PAF biosynthetic enzyme, is upregulated in human pancreatic cancer and shows unfavorable correlation with patient survival across multiple cancer types. Out study identifies PAF as lipid-driven mechanism of MDSC differentiation. Funding Sources National Institutes of Health grant Al102851 National Institutes of Health grant Al147362 National Institutes of Health grant HL160723 National Institutes of Health grant T32 GM007356 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)