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

• Published in: Oncotarget Vol. 6; no. 40; pp. 43005 - 43015
• Main Authors: Soares, Kevin C, Rucki, Agnieszka A, Kim, Victoria, Foley, Kelly, Solt, Sara, Wolfgang, Christopher L, Jaffee, Elizabeth M, Zheng, Lei
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 15.12.2015
• Subjects: 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; Mice; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Research Paper; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - antagonists & inhibitors; regulatory T cells; TGF-beta; pancreatic cancer; vaccine; immunotherapy
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5656

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.