Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer

Nat Immunol. 2001 Oct;2(10):962-70. doi: 10.1038/ni1001-962.


We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the widely expressed human MDM2 oncoprotein and were able to bypass self-tolerance to this tumor antigen in HLA-A*0201 (A2.1) transgenic mice and by generating A2.1-negative, allo-A2.1-restricted human T lymphocytes. A broad range of malignant, as opposed to nontransformed cells, were killed by high-avidity transgenic mouse and allogeneic human CTLs specific for the A2.1-presented MDM2 epitope. Whereas the self-A2.1-restricted human T cell repertoire gave rise only to low-avidity CTLs unable to recognize the natural MDM2 peptide, human A2.1+ T lymphocytes were turned into efficient MDM2-specific CTLs upon expression of wild-type and partially humanized high-affinity T cell antigen receptor (TCR) genes derived from the transgenic mice. These results demonstrate that TCR gene transfer can be used to circumvent self-tolerance of autologous T lymphocytes to universal tumor antigens and thus provide the basis for a TCR gene transfer-based broad-spectrum immunotherapy of malignant disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Cell Line
  • Cytotoxicity Tests, Immunologic
  • Epitopes, T-Lymphocyte / immunology
  • Genes, T-Cell Receptor*
  • Genetic Therapy*
  • HLA-A2 Antigen / genetics
  • Humans
  • Immunotherapy, Adoptive
  • Leukemia / immunology
  • Leukemia / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • Nuclear Proteins*
  • Proto-Oncogene Proteins / immunology*
  • Proto-Oncogene Proteins c-mdm2
  • Self Tolerance*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transduction, Genetic
  • Tumor Cells, Cultured


  • Antigens, Neoplasm
  • Epitopes, T-Lymphocyte
  • HLA-A2 Antigen
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2