TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner

// Kevin C. Soares 1, 3, 4, 5, 6 , Agnieszka A. Rucki 1, 4, 5, 6 , Victoria Kim 1, 3, 4, 5, 6 , Kelly Foley 4, 5, 6 , Sara Solt 4, 5, 6 , Christopher L. Wolfgang 1, 3, 4, 6 , Elizabeth M. Jaffee 1, 2, 4, 5, 6 , Lei Zheng 1, 3, 4, 5, 6 1 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA 5 The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA 6 The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA Correspondence to: Lei Zheng, e-mail: lzheng6@jhmi.edu Keywords: vaccine, pancreatic cancer, immunotherapy, TGF-beta, regulatory T cells Received: July 12, 2015      Accepted: September 12, 2015      Published: October 15, 2015 ABSTRACT 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.