This Article Full Text Full Text (PDF) Supplementary Data 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 Google Scholar Google Scholar Articles by Bioley, G. Articles by Ayyoub, M. Search for Related Content PubMed PubMed Citation Articles by Bioley, G. Articles by Ayyoub, M.

HLA Class I–Associated Immunodominance Affects CTL Responsiveness to an ESO Recombinant Protein Tumor Antigen Vaccine

Authors' Affiliations: ¹ Institut National de la Santé et de la Recherche Médicale, U892, CLCC René Gauducheau, Saint Herblain, France; ² Faculty of Medicine, University of Nantes, Nantes, France; ³ Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; ⁴ Immunology Program, Department of Medicine, ⁵ Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, ⁶ Departments of Pathology, Medicine, and Dermatology, New York University School of Medicine, NYU Medical Center, and ⁷ Division of Medical Oncology, Columbia University Medical Center, New York, New York

Requests for reprints: Danila Valmori, INSERM U892, CLCC René Gauducheau, Boulevard Jacques Monod, 44800 Saint Herblain, France. Phone: 33-2-40-67-97-26; Fax: 33-2-40-67-97-63; E-mail: Danila.Valmori{at}univ-nantes.fr or Maha Ayyoub, Phone: 33-2-40-67-97-25; Fax: 33-2-40-67-97-63; E-mail: Maha.Ayyoub{at}univ-nantes.fr.

Purpose: Vaccination with full-length human tumor antigens aims at inducing or increasing antitumor immune responses, including CD8 CTL in cancer patients across the HLA barrier. We have recently reported that vaccination with a recombinant tumor-specific NY-ESO-1 (ESO) protein, administered with Montanide and CpG resulted in the induction of specific integrated antibody and CD4 T cell responses in all vaccinated patients examined, and significant CTL responses in half of them. Vaccine-induced CTL mostly recognized a single immunodominant region (ESO 81-110). The purpose of the present study was to identify genetic factor(s) distinguishing CTL responders from nonresponders.

Experimental Design: We determined the HLA class I alleles expressed by CTL responders and nonresponders using high-resolution molecular typing. Using short overlapping peptides spanning the ESO immunodominant CTL region and HLA class I/ESO peptide tetramers, we determined the epitopes recognized by the majority of vaccine-induced CTL.

Results: CTL induced by vaccination with ESO protein mostly recognized distinct but closely overlapping epitopes restricted by a few frequently expressed HLA-B35 and HLA-Cw3 alleles. All CTL responders expressed at least one of the identified alleles, whereas none of the nonresponders expressed them.

Conclusions: Expression of HLA-B35 and HLA-Cw3 is associated with the induction of immunodominant CTL responses following vaccination with recombinant ESO protein. Because recombinant tumor-specific proteins are presently among the most promising candidate anticancer vaccines, our findings indicate that the monitoring of cancer vaccine trials should systematically include the assessment of HLA association with responsiveness.