American Association for Cancer Research
15357163mct180850-sup-206162_2_supp_5194156_pj0d2s.pdf (118.27 kB)

Figure S4 from TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

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journal contribution
posted on 2023-04-03, 15:11 authored by Daniel R. Principe, Alex Park, Matthew J. Dorman, Sandeep Kumar, Navin Viswakarma, Jonathan Rubin, Carolina Torres, Ronald McKinney, Hidayatullah G. Munshi, Paul J. Grippo, Ajay Rana

Figure S4 shows gross changes in tissue architecture, length, and weight in control and Galunisertib/anti-PD-1 treated mice.



Veterans Affairs Merit Award



Pancreatic ductal adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of 8%. This is mainly attributed to the late stage of presentation, as well as widespread resistance to conventional therapy. In addition, PDAC tumors are largely nonimmunogenic, and most patients have displayed incomplete responses to cancer immunotherapies. Our group has previously identified TGFβ as a crucial repressor of antitumor immune function in PDAC, particularly with respect to cytotoxic T lymphocytes. However, pharmacologic inhibition of TGFβ signaling has had limited efficacy in clinical trials, failing to promote a significant antitumor immune response. Hence, in this work, we extend our analysis to identify and circumvent the mechanisms of resistance to TGFβ signal inhibition in PDAC. Consistent with our previous observations, adoptive transfer of TGFβ-insensitive CD8+ T cells led to the near complete regression of neoplastic disease in vivo. However, we demonstrate that this cannot be recapitulated via global reduction in TGFβ signaling, through either genetic ablation or pharmacologic inhibition of TGFBR1. In fact, tumors with TGFβ signal inhibition displayed increased PD-L1 expression and had no observable change in antitumor immunity. Using genetic models of advanced PDAC, we then determined that concomitant inhibition of both TGFβ and PD-L1 receptors led to a reduction in the neoplastic phenotype, improving survival and reducing disease-associated morbidity in vivo. Combined, these data strongly suggest that TGFβ and PD-L1 pathway inhibitors may synergize in PDAC, and this approach warrants clinical consideration.