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

Oncotarget. 2015 Dec 15;6(40):43005-15. doi: 10.18632/oncotarget.5656.

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-g 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.

Keywords: TGF-beta; immunotherapy; pancreatic cancer; regulatory T cells; vaccine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Neutralizing / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cancer Vaccines / administration & dosage*
  • Carcinoma, Pancreatic Ductal / immunology*
  • Carcinoma, Pancreatic Ductal / pathology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Mesothelin
  • Mice
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / antagonists & inhibitors

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Cancer Vaccines
  • GVAX vaccine
  • Msln protein, mouse
  • Transforming Growth Factor beta
  • Mesothelin