T cell recognition of HLA-A2 restricted tumor antigens is impaired by the oncogene HER2.
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.
Mimura
Kousaku
K
Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Ando
Takashi
T
Poschke
Isabel
I
Mougiakakos
Dimitrios
D
Johansson
C Christian
CC
Ichikawa
Jiro
J
Okita
Riki
R
Nishimura
Michael I
MI
Handke
Diana
D
Krug
Nancy
N
Choudhury
Aniruddha
A
Seliger
Barbara
B
Kiessling
Rolf
R
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
D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human