Identification of HER2/neu-derived peptide epitopes recognized by gastric cancer-specific cytotoxic T lymphocytes.
We have derived HLA-A2.1-restricted, gastric cancer-specific cytotoxic T lymphocyte (CTL) lines by repetitive in vitro stimulation of tumor-associated lymphocytes (TAL) with autologous tumor cells. The HER2/neu specificity of these gastric cancer-specific CTLs was demonstrated using HER2/neu-transfected cell lines and HER2/neu-expressing tumors, and with a set of HER2/neu-derived peptide epitopes. Gastric cancer-specific CTLs specifically lysed autologous and allogeneic HLA-A2.1+, HER2/neu+ gastric cancer cells, HER2/neu-transfected C1R/A2 cell lines (HLA-A2.1+, HER2+) and HLA-A2.1-transfected SW626 tumor cell lines (HLA-A2.1+, HER2+). This recognition could be inhibited by anti-HLA-A2 antibody or by cold target HER2/neu-transfected C1R/A2 cells. Our results demonstrate that the HER2/neu-encoded HLA-A2.1-associated epitopes recognized by CTLs are presented as naturally processed peptides on gastric cancer lines. Furthermore, 3 of 19 tested HER2/neu-derived peptide epitopes [HER2(9(106)), HER2(9(369)), HER2(9(689))], which all bound HLA-A2.1 with high (IC50 < 50 nM) affinity, were able to sensitize HLA-A2+ C1R/A2 cells to be recognized by the gastric cancer-specific CTLs, demonstrating the immunodominance of these epitopes. In conclusion, our findings implicate HER2/neu-derived epitopes as potential candidates for novel immunotherapy and vaccine strategies against gastric cancer.
Kono
K
K
First Department of Surgery, Yamanashi Medical University, Japan. kojikono@res.yamanashi-med.ac.jp
Rongcun
Y
Y
Charo
J
J
Ichihara
F
F
Celis
E
E
Sette
A
A
Appella
E
E
Sekikawa
T
T
Matsumoto
Y
Y
Kiessling
R
R
D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D012680:Sensitivity and Specificity; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D018719:Erb-b2 Receptor Tyrosine Kinases