MAGE-C2-Specific TCRs Combined with Epigenetic Drug-Enhanced Antigenicity Yield Robust and Tumor-Selective T Cell Responses

J Immunol. 2016 Sep 15;197(6):2541-52. doi: 10.4049/jimmunol.1502024. Epub 2016 Aug 3.


Adoptive T cell therapy has shown significant clinical success for patients with advanced melanoma and other tumors. Further development of T cell therapy requires improved strategies to select effective, yet nonself-reactive, TCRs. In this study, we isolated 10 TCR sequences against four MAGE-C2 (MC2) epitopes from melanoma patients who showed clinical responses following vaccination that were accompanied by significant frequencies of anti-MC2 CD8 T cells in blood and tumor without apparent side effects. We introduced these TCRs into T cells, pretreated tumor cells of different histological origins with the epigenetic drugs azacytidine and valproate, and tested tumor and self-reactivities of these TCRs. Pretreatment of tumor cells upregulated MC2 gene expression and enhanced recognition by T cells. In contrast, a panel of normal cell types did not express MC2 mRNA, and similar pretreatment did not result in recognition by MC2-directed T cells. Interestingly, the expression levels of MC2, but not those of CD80, CD86, or programmed death-ligand 1 or 2, correlated with T cell responsiveness. One of the tested TCRs consistently recognized pretreated MC2(+) cell lines from melanoma, head and neck, bladder, and triple-negative breast cancers but showed no response to MHC-eluted peptides or peptides highly similar to MC2. We conclude that targeting MC2 Ag, combined with epigenetic drug-enhanced antigenicity, allows for significant and tumor-selective T cell responses.

MeSH terms

  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Azacitidine / pharmacology
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology
  • B7-2 Antigen / genetics
  • B7-2 Antigen / immunology
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Cell Line, Tumor
  • Epitopes, T-Lymphocyte / immunology
  • Humans
  • Immunotherapy, Adoptive
  • Lymphocyte Activation
  • Melanoma / immunology*
  • Melanoma / pathology
  • Melanoma / therapy
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Valproic Acid / pharmacology


  • Antigens, Neoplasm
  • B7-1 Antigen
  • B7-2 Antigen
  • B7-H1 Antigen
  • CD274 protein, human
  • CD86 protein, human
  • Epitopes, T-Lymphocyte
  • MAGEC2 protein, human
  • Neoplasm Proteins
  • Receptors, Antigen, T-Cell
  • Valproic Acid
  • Azacitidine