TGFb blockade augments PD-1 inhibition to promote T-cell–mediated regression of pancreatic cancer

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

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

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 TGFb as a crucial repressor of antitumor immune function in PDAC, particularly with respect to cytotoxic T lymphocytes. However, pharmacologic inhibition of TGFb 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 TGFb signal inhibition in PDAC. Consistent with our previous observations, adoptive transfer of TGFb-insensitive CD8þ 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 TGFb signaling, through either genetic ablation or pharmacologic inhibition of TGFBR1. In fact, tumors with TGFb 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 TGFb 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 TGFb and PD-L1 pathway inhibitors may synergize in PDAC, and this approach warrants clinical consideration.

Original languageEnglish (US)
Pages (from-to)613-620
Number of pages8
JournalMolecular cancer therapeutics
Volume18
Issue number3
DOIs
StatePublished - Mar 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Principe, D. R., Park, A., Dorman, M. J., Kumar, S., Viswakarma, N., Rubin, J., Torres, C., McKinney, R., Munshi, H. G., Grippo, P. J., & Rana, A. (2019). TGFb blockade augments PD-1 inhibition to promote T-cell–mediated regression of pancreatic cancer. Molecular cancer therapeutics, 18(3), 613-620. https://doi.org/10.1158/1535-7163.MCT-18-0850