TNF and inflammation

Abstract public domain (NIH RePORTER)

Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DC). Previous work from our laboratory found that TNF enhanced PDAC aggressiveness, but how it did so was unknown. Our current studies used several genetically engineered mouse models to explore this question. KPC mice develop oncogenic K-ras-driven PDAC that closely resembles the human disease, and were used as both a source of transplantable tumors as well as an in vivo model of spontaneous tumor generation. The contribution of the two TNF receptors, TNFR1 and TNFR2, was assessed with the corresponding knockout mice, as well as by antibody-mediated blockade. We found that signaling via TNFR1, but not TNFR2, dramatically accelerated PDAC growth and mouse mortality. Single cell transcriptomic analyses of tumor-infiltrating immune cells revealed that in the absence of TNFR1 signaling there was a marked increase in the number of antigen-presenting DC and a corresponding increase in activated T cells. In Rag-knockout mice, which lack T and B cells, TNFR1 blockade still resulted in increased DC infiltration but had no effect on tumor progression, suggesting that TNF primarily acts on DC to limit their numbers, resulting in local immunosuppression. This is consistent with our finding that TNF induced apoptosis of in vitro generated bone marrow-derived DC. Treatment of PDAC with anti-TNFR1 was more effective than the combination of Flt3L and agonistic anti-CD40 antibodies, another approach to enhancing intra-tumor DC number and function, perhaps because the latter increased whereas anti-TNFR1 decreased tumor expression of immunosuppressive PD-L1. Thus, intra-tumor TNF is a major pro-tumorigenic factor that signals via TNFR1 to limit tumor-infiltrating DC number and function. Current FDA approved "anti-TNF" therapies block TNF signaling via both of its receptors, which may have opposing effects on T cell function. Our results suggest that TNFR1 may be an attractive therapeutic target in human PDAC.