Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation

Cancer Immunol Res. 2014 Jul;2(7):616-31. doi: 10.1158/2326-6066.CIR-14-0027. Epub 2014 Jun 18.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered a "nonimmunogenic" neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other "nonimmunogenic" tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a "nonimmunogenic" neoplasm into an "immunogenic" neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1-PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naïve patients for immune checkpoint and other immunomodulatory therapies.

Publication types

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

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Adenocarcinoma / therapy*
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Cancer Vaccines / therapeutic use*
  • Cell Aggregation / immunology
  • Chemotherapy, Adjuvant
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / therapeutic use
  • Drug Administration Schedule
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Interferon-gamma / biosynthesis
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / therapy*
  • T-Lymphocytes, Regulatory / immunology
  • Up-Regulation / immunology

Substances

  • Antineoplastic Agents, Alkylating
  • Cancer Vaccines
  • GVAX vaccine
  • Interferon-gamma
  • Cyclophosphamide

Supplementary concepts

  • Pancreatic Carcinoma