TNFR1 expression on cancer cells mediates immune escape and an immunosuppressive microenvironment

<jats:p>TNFα is a proinflammatory cytokine that can mediate immunosuppressive effects in cancer. Tumors in which we silenced TNFR1 by CRISPR/Cas9 showed that TNFR1KO variants poorly engrafted in immunocompetent hosts, while engraftment in immunodeficient or CD8 T lymphocyte–depleted mice was preserved. The mechanism was mediated by secondary chemotactic inflammatory mediators elicited by TNFα in the malignant cells themselves. As a result, TNFR1KO variants recruited drastically fewer myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment, thus explaining the immune escape of the WT variants. Interestingly, small amounts of TNFR1-sufficient tumor cells co-engrafted with the TNFR1KO variants rescued tumorigenicity in the same tumor lesion but not in distantly implanted TNFR1KO tumors. Secondary mediators chiefly include CXCR1/2-acting chemokines, prostaglandin E2 and TNFα itself. Knocking down TNFR1 in a human tumor cell line rendered comparable MDSC-recruiting results when xenografted. Analyses of scRNA-seq and spatial transcriptomics datasets from human solid tumors corroborate the role of TNFR1 on tumor cells in the induction of secondary pro-tumor inflammatory mediators.</jats:p>