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Identification of an Immunogenic CTL Epitope of HIFPH3 for Immunotherapy of Renal Cell Carcinoma

Authors' Affiliations: Departments of ¹ Urology, ² Pathology, and ³ Diagnostic Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan and ⁴ Dainippon Sumitomo Pharma, Co. Ltd., Osaka, Japan

Requests for reprints: Toshihiko Torigoe, Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17 chuo-ku, Sapporo 060-8556, Japan. Phone: 81-11-613-8374; Fax: 81-11-643-2310; E-mail: torigoe{at}sapmed.ac.jp.

Purpose: CD8⁺ CTLs have an essential role in immune response against tumor. Although tumor-associated antigens have been identified in renal cell carcinoma (RCC), few of these are commonly shared and investigated as therapeutic targets in the clinical medicine. In this report, we show that HIFPH3, a member of prolyl hydroxylases that function as oxygen sensor, is a novel tumor antigen and HIFPH3-specific CTLs are induced from peripheral blood lymphocytes of RCC patients.

Experimental Design: Expression of HIFPH3 was examined by reverse transcription-PCR and immunostaining with anti-HIFPH3 antibody. To identify HLA-A24-restricted T-cell epitopes of HIFPH3, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. Peptide-specific CTLs were induced by stimulating peripheral blood lymphocytes of HLA-A24-positive RCC patients with these peptides in vitro. HLA-A24-restricted cytotoxicity of the CTLs against HIFPH3⁺ RCC lines was assessed by chromium release assay.

Results: HIFPH3 was overexpressed in many RCC cell lines and primary RCC tissues, whereas it was not detectable in normal adult tissues by reverse transcription-PCR. Of the eight peptides that contained HLA-A24-binding motif, HIFPH3-8 peptide (amino acid sequence, RYAMTVWYF) could induce the peptide-specific CTLs from 3 of 6 patients with HIFPH3-positive RCC. Furthermore, HIFPH3-8 peptide-specific CTLs showed cytotoxicity against HIFPH3⁺ RCC cell lines in a HLA-A24-restricted manner.

Conclusions: HIFPH3 may be a target antigen in immunotherapy for RCC and HIFPH3-8 peptide could be used as a peptide vaccine for HLA-A*2402⁺/HIFPH3⁺ RCC patients.