Peptides derived from human insulin‐like growth factor‐II mRNA binding protein 3 can induce human leukocyte antigen‐A2‐restricted cytotoxic T lymphocytes reactive to cancer cells

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‐3 515 NLSSAEVVV 523 were reproducibly established from HLA‐A2‐positive healthy donors and lung cancer patients. On the other hand, IMP‐3 199 RLLVPTQFV 207 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)