title: HLA-G as a target molecule in specific immunotherapy against renal cell carcinoma.
abstract: The human leukocyte antigen (HLA)-G molecule can exert immunoregulatory functions. However, its limited tissue distribution and preferential expression in a variety of malignancies suggest the possibility that it could be a target in anti-cancer immunotherapy. In the present study, we tested this possibility by focusing on renal cell carcinoma (RCC) patients, especially those with HLA-A24 alleles. Four HLA-G-derived peptides were prepared based on the binding motif to the HLA-A24 alleles. After a stabilization assay confirmed the binding of these peptides to HLA-A24 molecules, they were screened for the capacity to induce peptide-specific cytotoxic T lymphocytes (CTLs) from peripheral blood mononuclear cells (PBMCs) of HLA-A24+ RCC cancer patients. As a result, the HLA-G(146-154) peptide was found to effectively induce peptide-specific CTLs, and HLA-G(146-154) peptide-stimulated PBMCs exhibited cytotoxic activity against HLA-G-expressing HLA-A24+ RCC cells. Antibody blocking and cold inhibition experiments confirmed that the cytotoxicity was partially ascribed to peptide-specific and HLA class I-restricted CD8+ T cells. These results indicate that HLA-G-associated immunoregulation can be overcome and that HLA-G peptide-based anti-cancer immunotherapy is feasible.
authors.affiliation: Cancer Vaccine Development Division, Kurume University Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan. ycomo@kumamoto-u.ac.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.forename: Mamoru
authors.initials: M
authors.lastname: Harada
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Suekane
authors.forename: Masanori
authors.initials: M
authors.lastname: Noguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Yamada
authors.forename: Kei
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Kyogo
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000595:Amino Acid Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics; D059871:HLA-A24 Antigen; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
chemical_list: D006680:HLA Antigens; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D007371:Interferon-gamma