This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Komori, H. Articles by Nishimura, Y. Search for Related Content PubMed PubMed Citation Articles by Komori, H. Articles by Nishimura, Y.

Identification of HLA-A2- or HLA-A24-Restricted CTL Epitopes Possibly Useful for Glypican-3-Specific Immunotherapy of Hepatocellular Carcinoma

Authors' Affiliations: Departments of ¹ Immunogenetics and ² Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University; ³ Department of Microbiology, Saitama Medical School, Saitama; and ⁴ Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan

Requests for reprints: Yasuharu Nishimura, Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan. Phone: 81-96-373-5310, Fax: 81-96-373-5314; E-mail: mxnishim{at}gpo.kumamoto-u.ac.jp.

Purpose and Experimental Design: We previously reported that glypican-3 (GPC3) was overexpressed, specifically in hepatocellular carcinoma (HCC) and melanoma in humans, and it was useful as a novel tumor marker. We also reported that the preimmunization of BALB/c mice with dendritic cells pulsed with the H-2K^d-restricted mouse GPC3_298-306 (EYILSLEEL) peptide prevented the growth of tumor-expressing mouse GPC3. Because of similarities in the peptide binding motifs between H-2K^d and HLA-A24 (A*2402), the GPC3_298-306 peptide therefore seemed to be useful for the immunotherapy of HLA-A24⁺ patients with HCC and melanoma. In this report, we investigated whether the GPC3_298-306 peptide could induce GPC3-reactive CTLs from the peripheral blood mononuclear cells (PBMC) of HLA-A24 (A*2402)⁺ HCC patients. In addition, we used HLA-A2.1 (HHD) transgenic mice to identify the HLA-A2 (A*0201)–restricted GPC3 epitopes to expand the applications of GPC3-based immunotherapy to the HLA-A2⁺ HCC patients.

Results: We found that the GPC3_144-152 (FVGEFFTDV) peptide could induce peptide-reactive CTLs in HLA-A2.1 (HHD) transgenic mice without inducing autoimmunity. In five out of eight HLA-A2⁺ GPC3⁺ HCC patients, the GPC3_144-152 peptide-reactive CTLs were generated from PBMCs by in vitro stimulation with the peptide and the GPC3_298-306 peptide-reactive CTLs were also generated from PBMCs in four of six HLA-A24⁺ GPC3⁺ HCC patients. The inoculation of these CTLs reduced the human HCC tumor mass implanted into nonobese diabetic/severe combined immunodeficiency mice.

Conclusion: Our study raises the possibility that these GPC3 peptides may therefore be applicable to cancer immunotherapy for a large number of HCC patients.

This article has been cited by other articles:

				P. Blancou, R. Mallone, E. Martinuzzi, S. Severe, S. Pogu, G. Novelli, G. Bruno, B. Charbonnel, M. Dolz, L. Chaillous, et al. Immunization of HLA Class I Transgenic Mice Identifies Autoantigenic Epitopes Eliciting Dominant Responses in Type 1 Diabetes Patients J. Immunol., June 1, 2007; 178(11): 7458 - 7466. [Abstract] [Full Text] [PDF]