TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function.

Muhammad S Alam, Matthias M Gaida, Hagen R Witzel, Shizuka Otsuka, Aamna Abbasi, Theresa Guerin, Abdalla Abdelmaksoud, Nathan Wong, Margaret C Cam, Serguei Kozlov, Jonathan D Ashwell

Cell reports. Medicine 2024 Sep 17

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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. Published by Elsevier Inc.

Citation

Muhammad S Alam, Matthias M Gaida, Hagen R Witzel, Shizuka Otsuka, Aamna Abbasi, Theresa Guerin, Abdalla Abdelmaksoud, Nathan Wong, Margaret C Cam, Serguei Kozlov, Jonathan D Ashwell. TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function. Cell reports. Medicine. 2024 Sep 17;5(9):101696