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Ran, a Small GTPase Gene, Encodes Cytotoxic T Lymphocyte (CTL) Epitopes Capable of Inducing HLA-A33–restricted and Tumor-Reactive CTLs in Cancer Patients

¹ Department of Immunology and Research Center of Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science, Kurume University School of Medicine, Kurume; Departments of ² Surgery and ³ Pathology, Tazuke-Kofukai Kitano Hospital, Osaka; and ⁴ Department of General Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Purpose: The purpose is to identify a gene coding for tumor-associated antigen and peptide capable of inducing CTLs reactive to tumor cells with a HLA-A33–restricted fashion to provide scientific basis for specific immunotherapy to HLA-A33⁺ cancer patients.

Experimental Design: An expression gene-cloning method was used to identify the tumor-associated antigen gene. Northern blot analysis and immunohistochemistry were used to examine the mRNA and protein expression levels in various cells and tissues, respectively. Synthetic peptides were examined for their ability to induce HLA-A33⁺ tumor-reactive CTLs in peripheral blood mononuclear cells from cancer patients.

Result: A gene of small GTPase, Ran, which controls the cell cycle through the regulation of nucleocytoplasmic transport, mitotic spindle organization, and nuclear envelope formation, was found to encode epitopes recognized by the HLA-A33–restricted CTLs established from T cells infiltrating into gastric adenocarcinoma. The expression of the Ran gene was increased in most cancer cell lines and cancer tissues at both the mRNA and protein levels. However, it was not enhanced in the surrounding normal cells or tissues. It was also undetectable in normal tissues as far as tested. Ran-derived peptides at positions 48–56 and 87–95 could induce CD8⁺ peptide-specific CTLs reactive to tumor cells from HLA-A33⁺ epithelial cancer patients in a HLA class I-restricted manner.

Conclusions: Because of its increased expression in cancer cells and involvement in malignant transformation and/or the enhanced proliferation of cancer cells, the two Ran-directed peptides could be potent candidates in use for specific immunotherapy against HLA-A33⁺ epithelial cancers.

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