One NY-ESO-1-Derived Epitope That Promiscuously Binds to Multiple HLA-DR and HLA-DP4 Molecules and Stimulates Autologous CD4+ T Cells from Patients with NY-ESO-1-Expressing Melanoma

Abstract

NY-ESO-1 is expressed by a broad range of human tumors and is often recognized by Abs in the sera of cancer patients with NY-ESO-1-expressing tumors. The NY-ESO-1 gene also encodes several MHC class I- and class II-restricted tumor epitopes recognized by T lymphocytes. In this study we report one novel pan-MHC class II-restricted peptide sequence, NY-ESO-1 87–111, that is capable of binding to multiple HLA-DR and HLA-DP4 molecules, including HLA-DRB1*0101, 0401, 0701, and 1101 and HLA-DPB1*0401 and 0402 molecules. We also demonstrate that peptide NY-ESO-1 87–111 stimulates Th1-type and Th-2/Th0-type CD4+ T cells and clones when presented in the context of these HLA-DR and HLA-DP4 molecules. Both bulk CD4+ T cells and CD4+ T cell clones were capable of recognizing not only peptide-pulsed APCs, but also autologous dendritic cells, either loaded with the NY-ESO-1 protein or transfected with NY-ESO-1 cDNAs. Using IFN-γ and IL-5 ELISPOT assays and PBL from patients with NY-ESO-1-expressing tumors, we observed the existence of Th1-type circulating CD4+ T cells recognizing peptide NY-ESO-1 87–111 in the context of HLA-DP4 molecules. Taken together, these data represent the first report of an HLA-DR- and HLA-DP-restricted epitope from a tumor Ag. They also support the relevance of cancer vaccine trials with peptides NY-ESO-1 87–111 in the large number of cancer patients with NY-ESO-1-expressing tumors.

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

“…We found no evidence of class I restriction in any CD4 þ clone as has been described previously Mitchell et al, 1993;Darrow et al, 1996). Restriction of MAGE epitopes via non-HLA-DR class II molecules as described previously is a more likely explanation for our findings (Schultz et al, 2000;Mandic et al, 2005). None of the CD4 þ T-cell clones established in this study secreted interferon-g in response to recipient-derived nonmelanoma cells.…”

Definition of Key Variables for the Induction of Optimal NY-ESO-1–Specific T Cells in HLA Transgene Mice

“…1, 2 and unpublished data). This is at variance with studies showing that in patients with ESO + malignancies the frequencies of CD4 + T cells specific for these epitopes are similar (27,28,37). This might be explained by the fact that the DCs that prime CD4 + T cells generate and present biased repertoires of ESO peptides, thus obscuring the actual immunogenicity of the peptides.…”

“…It is a cytosolic protein of 180 aa, and MHC I and MHC II epitopes have been extensively mapped (http://www.cancerimmunity.org/ peptidedatabase/Tcellepitopes.htm). For A2 the immunodominant epitope is 157-165 (157p), which is expressed by most tumor cells (2,3,26), and for DR1 various epitopes have been reported, for example, 123-137 (123p), 87-101 (87p), and 87-111 (27,28). Our investigations in this highly defined system showed that 1) efficient priming of CD8 + T cells in draining lymph nodes requires available Th1 cells and copresentation of strongly immunogenic MHC I and MHC II epitopes by the same mature DC; 2) the Th1 cytokines IL-2 and IFN-g, namely in combination, induce CCR5 surface expression on naive CD8 + T cells; 3) the chemokines CCL4 and CCL3 play differential roles in guiding Th1 cells to DCs and activated naive CD8 + T cells to DC-CD4 T cell conjugates, respectively; and 4) these chemoattractions and the strength of Th1 cell help determine the upregulation of S1P 1 on freshly primed CD8 + T cells and hence their exit from the draining lymph nodes into circulation.…”

“…Such clusters have also been observed and enumerated in another intravital imaging study (20) (25). As TAA we used the cancer germ line Ag NY-ESO-1 (ESO), which has been widely used in cancer vaccine trials, is broadly expressed on diverse tumor cells, and is highly immunogenic (3,(26)(27)(28). It is a cytosolic protein of 180 aa, and MHC I and MHC II epitopes have been extensively mapped (http://www.cancerimmunity.org/ peptidedatabase/Tcellepitopes.htm).…”

Human Tumor Antigen-Specific Helper and Regulatory T Cells Share Common Epitope Specificity but Exhibit Distinct T Cell Repertoire

“…We and others have previously shown that CGA-derived epitopes that represent tumor-specific T cell targets (27), give rise to spontaneous Th1-type CD4 + T cells isolated either from PBLs or TILs of cancer patients (24,28). However, such spontaneous CD4 + T cell responses are found in patients with progressive disease, questioning their role in promoting potent antitumor CTL functions.…”