Yoshiaki Miyagi

Recognition of the Lck tyrosine kinase as a tumor antigen by cytotoxic T lymphocytes of cancer patients with distant metastases

The Lck protein (p56lck), a src family tyrosine kinase that is essential for T cell development and function, is aberrantly expressed in metastatic colon cancers. p56lck seems to facilitate the malignant transformation of epithelial cells through initiation of anchorage‐independent proliferation. We demonstrate that the lck gene encodes antigenic epitopes recognized by the HLA class I‐restricted and tumor‐specific CTL of metastatic cancer patients. Lck peptides augmented CTL activity in peripheral blood mononuclear cells (PBMC) of colon and other epithelial cancer patients with distant metastases, but not those without distant metastases. CTL precursors recognizing the Lck peptide were identified in freshly prepared PBMC of patients with distant metastases, and their frequency was significantly augmented by stimulation with the peptide. Thus, Lck peptides could be useful in developing a specific immunotherapy for cancer patients with distant metastases.

Identification of SART3‐derived peptides capable of inducing HLA‐A2‐restricted and tumor‐specific CTLs in cancer patients with different HLA‐A2 subtypes

We recently identified the SART3 antigen encoding shared tumor epitopes recognized by HLA‐A2402‐restricted and tumor‐specific CTLs. Our study investigated whether the SART3 antigen encodes peptides recognized by the HLA‐A2‐restricted CTLs. The HLA‐A2‐restricted and tumor‐specific CTL line recognized COS‐7 cells co‐transfected with the SART3 gene and either HLA‐A0201, ‐A0206 or ‐A0207 cDNA but not those co‐transfected with the SART3 gene and HLA‐A2402 or ‐A2601 cDNA. The 2 SART3 peptides at positions 302 to 310 and 309 to 317 possessed the ability to induce HLA‐A2‐restricted and tumor‐specific CTLs from peripheral blood mononuclear cells of cancer patients with various histological types and different HLA‐A2 subtypes. Therefore, these 2 peptides could be useful for specific immunotherapy of a relatively large number of HLA‐A2+ cancer patients. Int. J. Cancer 88:633–639, 2000.

Identification of Lck-derived peptides capable of inducing HLA-A2-restricted and tumor-specific CTLS in cancer patients with distant metastases

The Lck protein (p56lck), a src family tyrosine kinase essential for T cell development and function, is aberrantly expressed in various types of cancers. We revealed recently that Lck can be a tumor antigen recognized by HLA‐A24‐restricted and tumor‐specific cytotoxic T lymphocytes (CTLs) of cancer patients with metastases. In this study, we tried to identify Lck‐derived epitopes capable of inducing HLA‐A2‐restricted and tumor‐specific CTLs in cancer patients. The tumor‐infiltrating lymphocytes (TILs) from 2 HLA‐A2 cancer patients were found to respond to COS‐7 cells when co‐transfected with the lck gene and either HLA‐A0201, ‐A0206, or A0207 cDNA. These TILs contained CTLs capable of recognizing either the Lck61–69, the Lck246–254, or the Lck422–430 peptide among 24 different peptides, all of which were prepared based on the HLA‐A2 binding motif. Importantly, in vitro sensitization with the latter 2 peptides induced tumor‐specific CTLs in HLA‐A2+ cancer patients with metastases, but not in those without metastases. Overall, the Lck246–254 and Lck422–430 peptides could be useful for specific immunotherapy of HLA‐A2+ cancer patients, especially with distant metastases.

Expression of tumor rejection antigens in colorectal carcinomas

The authors recently reported that the SART2 and SART3 antigens encode tumor epitopes recognized by HLA‐A24‐restricted and tumor‐specific cytotoxic T lymphocytes (CTLs) established from esophageal carcinoma patients. The current study investigated these antigens to explore a potential molecule for specific immunotherapy for colorectal carcinoma patients.

Serine Proteinase Inhibitor 9 Can Be Recognized by Cytotoxic T Lymphocytes of Epithelial Cancer Patients

Serine proteinase inhibitor 9 (PI–9) inhibits granzyme B‐mediated apoptosis and interleukin–lβ‐converting enzyme activity. In this study, we report that the PI–9 gene encodes antigenic epitopes recognized by the HLA‐A24–restricted and tumor‐reactive cytotoxic T lymphocytes (CTLs) of epithelial cancer patients. Screening of an autologous cDNA library using a CTL line recognizing HLA‐A24+ tumor cells resulted in the isolation of a cDNA, which had an identical coding region to the previously described PI–9 genes. PI–9 gene was expressed in approximately three‐fourths of epithelial cancer cell lines and all leukemic cell lines tested. It was also expressed in normal peripheral blood mononuclear cells (PBMCs), but not in a normal fibroblast cell line. CTL sublines contained T cells capable of recognizing the PI–9292–300 and PI–9348–356 peptides among 13 different peptides having the HLA‐A24 binding motifs. These two peptides were recognized by the CTL line in a dose‐dependent and HLA class‐I‐restricted manner, and also possessed the ability to induce HLA class I‐restricted and tumor‐reactive CTLs in PBMCs from HLA‐A24+ cancer patients. These results demonstrate that PI–9 is recognized by HLA class I‐restricted and tumor‐reactive CTLs of epithelial cancer patients.