T cell recognition of HLA-A2 restricted tumor antigens is impaired by the oncogene HER2

Int J Cancer. 2011 Jan 15;128(2):390-401. doi: 10.1002/ijc.25613. Epub 2010 Oct 13.


The HER2 oncogene is frequently over-expressed in human cancers and a promising target for immune therapy. Previous studies have shown that over-expression of mouse or rat HER2 leads to markedly reduced levels of major histocompatibility complex (MHC) class I and molecules of the antigen processing and presentation machinery (APM), thus resulting in a phenotype promoting tumor escape from the immune system. Our study focuses on analyzing the effect of HER2 on MHC class I antigen presentation and sensitivity to tumor-antigen specific cytotoxic T lymphocytes (CTLs) in HLA-A2.1(+) melanoma cell lines. We demonstrate significant inverse correlations both between the expression of HER2 and total MHC class I surface expression as well as between HER2 and HLA-A2. A significant reduction of HLA-A2 levels was found when melanoma and carcinoma cell lines were transfected with a human HER2 gene. A signaling-competent HER2 molecule was crucial for the observed HLA-A2 down-regulation, as transfectants expressing high levels of HER2 mutated in the tyrosine signaling domain did not show altered HLA-A2 expression. Importantly, the human melanoma cell line EST049 demonstrated reduced HER2 and melanoma antigen-specific recognition by CTLs upon HER2 transfection. In addition, high expression of HER2 prevented both IFN-γ mediated HLA-A2 up-regulation and improved recognition by HLA-A2-restricted CTLs in treated cells. Moreover, key APM molecules were down-regulated by HER2. These findings implicate that HER2 over-expressing tumors may be more prone to escape from HLA-A2 restricted CTLs suggesting that immunotherapy approaches inducing an integrated humoral, cellular and innate immune response would be most effective.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation
  • Antigens, Neoplasm / immunology*
  • Cell Line, Tumor
  • Genes, erbB-2 / physiology*
  • HLA-A2 Antigen / analysis
  • HLA-A2 Antigen / immunology*
  • Humans
  • Interferon-gamma / physiology
  • Melanoma / genetics
  • Melanoma / immunology*
  • Receptor, ErbB-2 / analysis
  • Receptor, ErbB-2 / immunology
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Escape


  • Antigens, Neoplasm
  • HLA-A2 Antigen
  • Interferon-gamma
  • ERBB2 protein, human
  • Receptor, ErbB-2