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The Alternative Open Reading Frame of LAGE-1 Gives Rise to Multiple Promiscuous HLA-DR-restricted Epitopes Recognized by T-helper 1-type Tumor-reactive CD4+ T Cells¹

Departments of Medicine and Melanoma Center [M. M., B. J., K. C., J. M. K., H. M. Z.] and Immunology [H. M. Z.], University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and Protein Engineering and Research Department, CEA-Saclay, 91191 Gif-sur-Yvette, France [C. A., S. V., D. G., B. M.]

The NY-ESO-1 and LAGE-1 genes are expressed by many human cancers, but not by normal tissues, with the exception of testis and placenta. The NY-ESO-1 and LAGE-1 genes give rise to multiple MHC class I and class II-presented epitopes derived from the open reading frames (ORF) 1 and 2. Here, we have investigated whether NY-ESO-1/LAGE-1 ORF2 encodes promiscuous MHC class II-restricted epitopes. Using a set of overlapping peptides from the ORF2 protein sequence and autologous dendritic cells (DCs) from normal donors and melanoma patients, we have identified three HLA-DRB1*0401-restricted peptide sequences from the LAGE-1 ORF2 that are capable of stimulating T-helper 1-type melanoma-reactive CD4+ T cells. From these bulk CD4+ T cells, we have generated CD4+ T-cell clones able to recognize not only peptide-pulsed DCs but also autologous DCs loaded with the LAGE-1 ORF2 protein. We have demonstrated that these peptides not only bind to multiple HLA-DR molecules apart from HLA-DRB1*0401 but also stimulate CD4+ T cells when presented in the context of these HLA-DR molecules. Furthermore, our binding data have delineated two additional sequences capable of broadly binding to multiple HLA-DR molecules. Altogether, these data support the immunogenicity of NY-ESO-1/LAGE-1 ORF2 gene products and clearly demonstrate their capability to stimulate T-helper 1 type CD4+ T cells. Because of the role of these cells in promoting long-lasting antitumor CTL responses, our data provide a rationale for cancer vaccine trials with peptides derived from the NY-ESO-1/LAGE-1 ORF2 for a large fraction of patients with NY-ESO-1/LAGE-1⁺ tumors.

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