TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner
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Kevin C. Soares1,3,4,5,6, Agnieszka A. Rucki1,4,5,6, Victoria Kim1,3,4,5,6, Kelly Foley4,5,6, Sara Solt4,5,6, Christopher L. Wolfgang1,3,4,6, Elizabeth M. Jaffee1,2,4,5,6, Lei Zheng1,3,4,5,6
1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
4The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
5The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA
6The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Lei Zheng, e-mail: [email protected]
Keywords: vaccine, pancreatic cancer, immunotherapy, TGF-beta, regulatory T cells
Received: July 12, 2015 Accepted: September 12, 2015 Published: October 15, 2015
Our neoadjuvant clinical trial of a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) revealed the development of tertiary lymphoid aggregates (TLAs) within the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment 2 weeks after GVAX treatment. Microarray studies revealed that multiple components of the TGF-β pathway were suppressed in TLAs from patients who survived greater than 3 years and who demonstrated vaccine-enhanced mesothelin-specific T cell responses. We tested the hypothesis that combining GVAX with TGF-β inhibitors will improve the anti-tumor immune response of vaccine therapy. In a metastatic murine model of pancreatic cancer, combination therapy with GVAX vaccine and a TGF-β blocking antibody improved the cure rate of PDA-bearing mice. TGF-β blockade in combination with GVAX significantly increased the infiltration of effector CD8+ T lymphocytes, specifically anti-tumor-specific IFN-f producing CD8+ T cells, when compared to monotherapy controls (all p < 0.05). TGF-β blockade alone did not deplete T regulatory cells (Tregs), but when give in combination with GVAX, GVAX induced intratumoral Tregs were depleted. Therefore, our PDA preclinical model demonstrates a survival advantage in mice treated with an anti-TGF-β antibody combined with GVAX therapy and provides strong rational for testing this combinational therapy in clinical trials.
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