HLA-G as a target molecule in specific immunotherapy against renal cell carcinoma.
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.
Komohara
Yoshihiro
Y
Cancer Vaccine Development Division, Kurume University Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan. ycomo@kumamoto-u.ac.jp
Harada
Mamoru
M
Ishihara
Yuki
Y
Suekane
Shigetaka
S
Noguchi
Masanori
M
Yamada
Akira
A
Matsuoka
Kei
K
Itoh
Kyogo
K
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
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