期刊
CANCER SCIENCE
卷 102, 期 1, 页码 71-78出版社
WILEY
DOI: 10.1111/j.1349-7006.2010.01780.x
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类别
资金
- Ministry of Education, Culture, Sports, Science, and Technology, Japan [17015035, 18014023]
- Ministry of Health, Labor and Welfare, Japan
- Onco Therapy Science Co.
- Graduate School of Medical Sciences, Kumamoto University
- Grants-in-Aid for Scientific Research [23510243] Funding Source: KAKEN
Insulin-like growth factor-II mRNA binding protein 3 (IMP-3) is an oncofetal protein expressed in various malignancies including lung cancer. This study aimed to identify immunogenic peptides derived from IMP-3 that can induce tumor-reactive and human leukocyte antigen (HLA)-A2 (A*02:01)-restricted cytotoxic T lymphocytes (CTL) for lung cancer immunotherapy. Forty human IMP-3-derived peptides predicted to bind to HLA-A2 were analyzed to determine their capacity to induce HLA-A2-restricted T cells in HLA-A2.1 (HHD) transgenic mice (Tgm). We found that three IMP-3 peptides primed HLA-A2-restricted CTL in the HLA-A2.1 Tgm. Among them, human CTL lines reactive to IMP-3 515NLSSAEVVV523 were reproducibly established from HLA-A2-positive healthy donors and lung cancer patients. On the other hand, IMP-3 199RLLVPTQFV207 reproducibly induced IMP-3-specific and HLA-A2-restricted CTL from healthy donors, but did not sensitize CTL in the HLA-A2.1 Tgm. Importantly, these two IMP-3 peptide-specific CTL generated from healthy donors and cancer patients effectively killed the cancer cells naturally expressing both IMP-3 and HLA-A2. Cytotoxicity was significantly inhibited by anti-HLA class I and anti-HLA-A2 monoclonal antibodies, but not by the anti-HLA-class II monoclonal antibody. In addition, natural processing of these two epitopes derived from the IMP-3 protein was confirmed by specific killing of HLA-A2-positive IMP-3-transfectants but not the parental IMP-negative cell line by peptide-induced CTL. This suggests that these two IMP-3-derived peptides represent highly immunogenic CTL epitopes that may be attractive targets for lung cancer immunotherapy. (Cancer Sci 2011; 102: 71-80).
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