Oncotarget

Research Papers:

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

Kevin C. Soares _, Agnieszka A. Rucki, Victoria Kim, Kelly Foley, Sara Solt, Christopher L. Wolfgang, Elizabeth M. Jaffee and Lei Zheng

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:43005-43015. https://doi.org/10.18632/oncotarget.5656

Metrics: PDF 2741 views  |   HTML 4198 views  |   ?  


Abstract

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

Correspondence to:

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

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 5656