title: Hypoxia-inducing factor (HIF)-1α-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+patients with renal cell carcinoma.
abstract: Hypoxic tumor microenvironment makes cancer cells to be therapy-resistant and hypoxia-inducing factors (HIFs) play a central role in hypoxic adaptation. Especially, renal cell carcinoma (RCC) is often associated with von Hippel-Lindau (VHL) gene mutations, leading to up-regulation of HIFs. However, from a different point of view, this suggests the possibility that HIFs could be promising targets in anti-cancer therapy. In this study, we searched for HIF-1α-derived peptides that are able to induce RCC-reactive cytotoxic T lymphocytes (CTLs) from HLA-A24+RCC patients. Among five peptides derived from HIF-1α, which were prepared based on the binding motif to the HLA-A24 allele, a HIF-1α278-287peptide induced peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24+RCC patients most effectively. In immunoblot assays, the expression of HIF-1α was lowly detected in whole and nuclear lysates of RCC cell lines even under normoxia (20% O2), and their expression in whole lysates was increased under hypoxia (1% O2). Additionally, HIF-1α278-287peptide-stimulated T cells showed a higher cytotoxicity against HLA-A24+HIF-1α-expressing RCC cells than against HLA-A24-HIF-1α-expressing RCC cells. The cytotoxicity was inhibited by the addition of HIF-1α278-287peptide-pulsed cold target cells. Altogether, these results indicate that the HIF-1α278-287peptide could be a candidate for peptide-based anti-cancer vaccines for HLA-A24+RCC patients.
authors.affiliation: Department of Urology, Kindai University School of Medicine, Osaka, Japan. Electronic address: minami@med.kindai.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Minami
authors.affiliation: Department of Urology, Kindai University School of Medicine, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsumura
authors.affiliation: Department of Urology, Kindai University School of Medicine, Osaka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Urology, Kindai University School of Medicine, Osaka, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Urology, Kindai University School of Medicine, Osaka, Japan.
authors.forename: Marco
authors.initials: M
authors.lastname: De Velasco
authors.affiliation: Department of Urology, Kindai University School of Medicine, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nozawa
authors.affiliation: Department of Urology, Kindai University School of Medicine, Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Immunology, Shimane University School of Medicine, Izumo, Shimane, Japan.
authors.forename: Nanae
authors.initials: N
authors.lastname: Harashima
authors.affiliation: Department of Immunology, Shimane University School of Medicine, Izumo, Shimane, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Urology, Kindai University School of Medicine, Osaka, Japan. Electronic address: huemura@med.kindai.ac.jp.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Uemura
mesh_terms: D019496:Cancer Vaccines / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002478:Cells, Cultured; D059871:HLA-A24 Antigen / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D059016:Tumor Microenvironment; D022223:Vaccines, Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D019496:Cancer Vaccines; C497442:HIF1A protein, human; D059871:HLA-A24 Antigen; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010446:Peptide Fragments; D022223:Vaccines, Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: CTL; HIF-1α; HLA-A24; Peptide; Renal cell carcinoma