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, Lei Zheng

Research output: Contribution to journalArticle

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-γ 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.

Original languageEnglish (US)
Pages (from-to)43005-43015
Number of pages11
JournalOncotarget
Volume6
Issue number40
DOIs
StatePublished - Jan 1 2015

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Keywords

  • Immunotherapy
  • Pancreatic cancer
  • Regulatory T cells
  • TGF-beta
  • Vaccine

ASJC Scopus subject areas

  • Oncology

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