TGF? Blockade Augments PD-1 Inhibition to Promote T-Cell-Mediated Regression of Pancreatic Cancer.

ABSTRACT: 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 TGF? as a crucial repressor of antitumor immune function in PDAC, particularly with respect to cytotoxic T lymphocytes. However, pharmacologic inhibition of TGF? 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 TGF? signal inhibition in PDAC. Consistent with our previous observations, adoptive transfer of TGF?-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 TGF? signaling, through either genetic ablation or pharmacologic inhibition of TGFBR1. In fact, tumors with TGF? 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 TGF? 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 TGF? and PD-L1 pathway inhibitors may synergize in PDAC, and this approach warrants clinical consideration.

SUBMITTER: Principe DR 

PROVIDER: S-EPMC6397698 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature