Abstract
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. 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. 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. 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.
Highlights
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
Whereas the first generation of molecularly defined candidate cancer vaccines have mostly used short synthetic peptides corresponding to tumor antigen – derived CTL epitopes presented by defined HLA class I alleles [9], among the most promising candidates presently under trial are those containing full-length tumor antigens, which can potentially induce specific immune responses in all patients, irrespective of their HLA type [10, 11]
HLA-B35 and HLA-Cw3 alleles are associated with the induction of CTL responses to rESO
Summary
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. 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. Whereas the first generation of molecularly defined candidate cancer vaccines have mostly used short synthetic peptides corresponding to tumor antigen – derived CTL epitopes presented by defined HLA class I alleles [9], among the most promising candidates presently under trial are those containing full-length tumor antigens, which can potentially induce specific immune responses in all patients, irrespective of their HLA type [10, 11]. We provide the first evidence that HLA-associated immunodominance plays a dominant role in vaccine-induced CTL responses to the recombinant ESO protein which is presently one of the most promising anticancer candidate vaccines. Only half of them showed detectable CTL responses, mostly directed against a single immunodominant region located in the central part of the protein (81 – 110; ref. 10)
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