TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function
Muhammad S. Alam, Matthias M. Gaida, Hagen Roland Witzel, Shizuka Otsuka, Aamna Abbasi, Theresa M. Guerin, Abdalla Abdelmaksoud, Nathan Wong, Maggie Cam, С. В. Козлов, Jonathan D. Ashwell
Abstract
Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits. • TNF has a pro-tumorigenic role in PDAC by limiting intratumor DC number and function • TNFR1 blockade increased DC-dependent anti-tumor immunity and inhibited tumor growth • Signaling via TNFR1 induced DC apoptosis in vitro Alam et al. found that in pancreatic ductal adenocarcinomas, the pro-inflammatory cytokine TNF-α signals via TNFR1, its major receptor, to prevent the infiltration and activation of antigen-presenting dendritic cells. These effects were prevented by TNFR1 blockade, resulting in increased T cell-mediated anti-tumor immunity and inhibition of tumor progression.