TNFR1 expression on cancer cells is critical for immune escape shaping an immunosuppressive tumor microenvironment

Tumors in which we silenced TNFR1 by CRISPR/Cas9 showed disability of the TNFR1 KO variants to engraft in immunocompetent hosts, whilst 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, TNFR1 KO variants recruited drastically fewer myeloid-derived suppressor cells 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 TNFR1 KO variants rescued tumorigenicity in the same tumor lesion but not in a distantly implanted TNFR1 KO tumor. Secondary mediators chiefly include CXCR1/2-acting chemokines, prostaglandin-E2 and TNFα itself.