Survey of naturally occurring CD4⁺ T cell responses against NY-ESO-1 in cancer patients: Correlation with antibody responses

Abstract

NY-ESO-1 is one of the most immunogenic proteins described in human cancers, based on its capacity to elicit simultaneous antibody and CD8⁺ T cell responses in vivo. Although HLA class II restricted epitopes from NY-ESO-1 have been identified, no broad survey has yet established the status of natural CD4⁺ T cell responses in cancer patients in relation to CD8⁺ and antibody responses. We used a recently developed general strategy for monitoring CD4⁺ responses that overcomes the need for prior knowledge of epitope or HLA restriction to analyze a series of 31 cancer patients and healthy donors for the presence of CD4⁺ T cells to NY-ESO-1, and related this response to NY-ESO-1 expression in tumor cells and serum antibodies to NY-ESO-1. None of the 18 patients that tested seronegative for NY-ESO-1 had detectable CD4⁺ T cell responses. On the contrary, 11 of 13 cancer patients with serum antibodies to NY-ESO-1 had polyclonal CD4⁺ T cell responses directed against various known and previously undescribed NY-ESO-1 epitopes. NY-ESO-1 peptide 80–109 was the most immunogenic, with 10 of 11 patients responding to this peptide. We show here that 12-mer determinants from NY-ESO-1 eliciting a CD4⁺ T cell response were peptide 87–98 with promiscuous HLA class II presentation, peptide 108–119 restricted by HLA-DP4, and peptides 121–132 and 145–156, both shorter epitopes from previously described HLA-DR4 peptides, also presented by HLA-DR7. This study represents the next step in compiling a comprehensive picture of the adaptive immune response to NY-ESO-1, and provides a general strategy for analyzing the CD4⁺ T cell response to other tumor antigens eliciting a humoral immune response.