TGFβ 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 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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 3 Pg. 613-620 (03 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 30587556 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• B7-H1 Antigen
• Cd274 protein, mouse
• Transforming Growth Factor beta
• Receptor, Transforming Growth Factor-beta Type I
• Tgfbr1 protein, mouse

Topics

• Adenocarcinoma (drug therapy, genetics, immunology, pathology)
• Animals
• B7-H1 Antigen (antagonists & inhibitors, genetics)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, immunology, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Humans
• Immunotherapy
• Mice
• Mice, Transgenic
• Receptor, Transforming Growth Factor-beta Type I (genetics)
• Signal Transduction (drug effects)
• T-Lymphocytes (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Transforming Growth Factor beta (antagonists & inhibitors, genetics)
• Tumor Microenvironment (drug effects)