Identification of a novel HLA-A 02:01-restricted cytotoxic T lymphocyte epitope derived from the EML4-ALK fusion gene.
Cancer immunotherapy is a promising new approach to cancer treatment. It has been demonstrated that a high number of tumor-specific cytotoxic T cells (CTLs) is associated with increased disease-specific survival in lung cancer patients. Identification of superior CTL epitopes from tumor antigens is essential for the development of immunotherapy for malignant tumors. The EML4-ALK fusion gene was recently identified in a subset of non-small cell lung cancers (NSCLCs). In this study we searched for HLA-A 02:01- and HLA-A 24:02‑restricted epitopes derived from EML4-ALK by screening predicted EML4-ALK‑derived candidate peptides for the induction of tumor‑reactive CTLs. Nine EML4-ALK‑derived peptides were selected by a computer algorithm based on a permissive HLA-A 02:01 or HLA-A 24:02 binding motif. One of the nine peptides induced peptide-specific CTLs from human peripheral blood mononuclear cells. We were able to generate a peptide‑specific CTL clone. This CTL clone specifically recognized peptide‑pulsed T2 cells and H2228 cells expressing HLA-A 02:01 and EML4-ALK that had been treated with IFN-γ 48 h prior to examination. CTL activity was inhibited by an anti-HLA‑class I monoclonal antibody (W6/32), consistent with a class I-restricted mechanism of cytotoxicity. These results suggest that this peptide (RLSALESRV) is a novel HLA-A 02:01-restricted CTL epitope and that it may be a new target for antigen-specific immunotherapy against EML4‑ALK-positive cancers.
Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
Mayuko
M
Yoshimura
Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
Yoshitaka
Y
Tada
Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
Kazuya
K
Ofuzi
Department of Gastroenterological Surgery, Tokyo Women's Medical University, Shinzyukuku, Tokyo 162-8666, Japan.
Masakazu
M
Yamamoto
Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
Tetsuya
T
Nakatsura
D000951:Antigens, Neoplasm / Q000378:metabolism*; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D053673:Glypicans / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism*; D059871:HLA-A24 Antigen / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; C522504:EML4-ALK fusion protein, human; D018984:Epitopes, T-Lymphocyte; C105937:GPC3 protein, human; D053673:Glypicans; C435939:HLA-A*02:01 antigen; C438506:HLA-A*24:02 antigen; D015789:HLA-A2 Antigen; D059871:HLA-A24 Antigen; D015514:Oncogene Proteins, Fusion; D010455:Peptides