title: T cell recognition of HLA-A2 restricted tumor antigens is impaired by the oncogene HER2.
abstract: 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.
authors: Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors: Kousaku
authors: K
authors: Mimura
authors: Takashi
authors: T
authors: Ando
authors: Isabel
authors: I
authors: Poschke
authors: Dimitrios
authors: D
authors: Mougiakakos
authors: C Christian
authors: CC
authors: Johansson
authors: Jiro
authors: J
authors: Ichikawa
authors: Riki
authors: R
authors: Okita
authors: Michael I
authors: MI
authors: Nishimura
authors: Diana
authors: D
authors: Handke
authors: Nancy
authors: N
authors: Krug
authors: Aniruddha
authors: A
authors: Choudhury
authors: Barbara
authors: B
authors: Seliger
authors: Rolf
authors: R
authors: Kiessling
mesh_terms: D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D018734:Genes, erbB-2 / Q000502:physiology*; D015789:HLA-A2 Antigen / Q000032:analysis / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000276:immunology; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape
chemical_list: D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human