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Two Proliferation-Related Proteins, TYMS and PGK1, Could Be New Cytotoxic T Lymphocyte-Directed Tumor-Associated Antigens of HLA-A2⁺ Colon Cancer

¹ Department of Immunology, Kurume University School of Medicine and ² Research Center of Innovative Cancer Therapy of the 21st Century COE Program for Medical Science, Kurume University, Kurume, Fukuoka, Japan

Purpose: The purpose of this work was to provide a scientific basis for specific immunotherapy of colon cancer.

Experimental Design: This study focused on identification of colon tumor-associated antigens and HLA-A2–restricted and tumor-reactive cytotoxic T lymphocytes (CTLs) generated from tumor-infiltrating lymphocytes of a colon cancer patient. A gene expression cloning method was used to identify genes coding for tumor antigens. Fifty-six peptides with HLA-A2–binding motifs encoded by these proteins were examined for their ability to induce HLA-A2–restricted and tumor-reactive CTLs.

Results: We identified the following three genes coding for proliferation-related proteins: thymidylate synthase (TYMS), which is involved in chemoresistance (5-fluorouracil); 5'-aminoimidazole-4-carboxamide-1-ß-D-ribonucleotide transfolmylase/inosinicase (AICRT/I); and phosphoglycerate kinase 1 (PKG1), which was secreted by tumor cells and involved in the angiogenic process. TYMS was preferentially expressed in tumor cells, whereas AICRT/I and PKG1 were equally expressed in both cancer cells and normal tissues at the mRNA level. Among 56 peptides with HLA-A2–binding motifs encoded by these proteins, 8 peptides were recognized by the CTLs, and 5 of 8 peptides were also recognized by the CTL precursors without ex vivo activation in the peripheral blood of colon cancer patients. Furthermore, four of them (one each from TYMS and PKG1 and two from AICRT/1) possessed the ability to induce HLA-A2–restricted and peptide-specific CTLs cytotoxic to colon tumor cells in peripheral blood mononuclear cells of colon cancer patients.

Conclusions: TYMS and PGK1, as well as their epitope peptides, might be appropriate target molecules for specific immunotherapy of HLA-A2⁺ colon cancer patients because of the positive role of TYMS and PGK1 in chemoresistance (5-fluorouracil) and angiogenesis of tumor cells, respectively.

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