Epigenetic modulation to enable antigen-specific T-cell therapy of colorectal cancer

Jeffrey Chou*, Lilien N. Voong, Christie L. Mortales, Andrea M.H. Towlerton, Seth M. Pollack, Xiaoji Chen, Cassian Yee, Paul F. Robbins, Edus H. Warren

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Development of specific immunotherapy for colorectal cancer (CRC) will require identification of antigens selectively or exclusively expressed on CRC cells and strategies to induce and enhance immune responses against these antigenic targets. Cancer-testis (C-T) antigens are proving to be excellent targets for immunotherapy of solid tumors such as melanoma, but their clinical utility for treatment of CRC has to date been limited by their infrequent expression in CRC cells. Here we report that the hypomethylating agent 5-aza-2′-deoxycytidine (DAC) induces expression of NY-ESO-1 and other C-T genes in CRC cells both in vitro and in vivo in a dose-dependent manner but has negligible effects on the expression of C-T genes in normal nontransformed cells such as fibroblasts. The induction by DAC of NY-ESO-1 expression in CRC cells persists over 100 days after DAC exposure and is associated with increased levels of NY-ESO-1 protein. CRC cells exposed to DAC at concentrations that can be readily achieved in vivo are rendered susceptible to major histocompatibility complex-restricted recognition by CD8 + NY-ESO-1-specific T cells. We also demonstrate that retroviral transduction of polyclonal peripheral blood T cells from a metastatic CRC patient with the T-cell receptor α-chain and β-chain genes encoding a human leukocyte antigen-A2-restricted, NY-ESO-1 157-165-specific T-cell receptor can be used to generate both CD8 + and CD4 + NY-ESO-1 157-165-specific T cells that selectively recognize DAC-treated CRC but not nontransformed cells. Collectively, these results suggest that the combination of epigenetic modulation and adoptive transfer of genetically engineered T lymphocytes may enable specific immunotherapy for CRC.

Original languageEnglish (US)
Pages (from-to)131-141
Number of pages11
JournalJournal of Immunotherapy
Volume35
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

Keywords

  • cancer-testis antigens
  • colorectal cancer
  • cytolytic T lymphocyte
  • NY-ESO-1
  • real-time cell electrical sensing assay

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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