Identification of an antigenic peptide derived from the cancer-testis antigen NY-ESO-1 binding to a broad range of HLA-DR subtypes

Abstract

NY-ESO-1 is a SEREX-defined cancer-testis antigen of which several MHC I, but only few MHC II-restricted epitopes have been identified. Searching for highly promiscuous MHC II-restricted peptides that might be suitable as a CD4+ stimulating vaccine for many patients, we used the SYFPEITHI algorithm and identified an NY-ESO-1-derived pentadecamer epitope (p134-148) that induced specific CD4+ T-cell responses restricted to the HLA-DRB1 subtypes *0101, *0301, *0401, and *0701 that have a cumulative prevalence of 40% in the Caucasian population. The DR restriction of the p134-148 pentadecamer was demonstrated by inhibition with an HLA-DR antibody and a functional peptide displacement titration assay with the pan-DR-binding T-helper epitope PADRE as the competitor. The natural processing and presentation of this epitope was demonstrated by recognition of an NY-ESO-1+ melanoma cell line by T cells with specificity for p134-148. The pentadecamer p134-148 was able to induce CD4+ responses in 4/38 cancer patients tested. However, no strict correlation was found between CD4+ T-cell responses against p134-148 reactivity and anti-NY-ESO-1 antibody titers in the serum of patients, suggesting that CD4+ and B-cell responses are regulated independently. In conclusion, p134-148 holds promise as a broadly applicable peptide vaccine for patients with NY-ESO-1-positive neoplasms.

Directions in the immune targeting of cancer: Lessons learned from the cancer‐testis Ag NY‐ESO‐1

“…The HLA-DR peptide recognizes a tumour pentadecamer epitope (p134-148). 83 A naturally processed HLA-A68-restricted T-cell epitope derived from LAGE-1 has now been described. 84 However, on a cautionary note, HLA-DR13-restricted epitopes derived from LAGE-1 have been shown to be ligands for CD4 1 regulatory T cells and to mediate inhibition of CD4 1 LAGE-1-specific T cells.…”

Heat Shock Protein 90-Mediated Peptide-Selective Presentation of Cytosolic Tumor Antigen for Direct Recognition of Tumors by CD4+ T Cells

“…Expression of MHC-II on tumors enables tumor Ag-specific CD4 + T cells to directly recognize tumors if MHC-II is loaded with tumor Ag peptides. Indeed, there are several reports demonstrating direct tumor recognition by CD4 + T cells (8)(9)(10), representing a nonclassical presentation pathway for endogenous protein from MHC-II-expressing tumors to CD4 + T cells (i.e., endogenous MHC-II presentation). However, the mechanism of endogenous MHC-II presentation from intracellular tumor Ags to MHC-II remains to be elucidated.…”

Identification of an epitope derived from the cancer testis antigen HOM-TES-14/SCP1 and presented by dendritic cells to circulating CD4+ T cells

“…Rather, for the present study and in light of the well-known promiscuous binding pattern of MHC class 2 peptides, it was advisable to include patients with unknown HLA status for the primary identification of CD4 ϩ T-cellstimulating epitopes. Although the HLA-DRB1*1401 restriction of the CD4 ϩ -mediated response to p635-649 has been established without any doubt by our experiments, a more promiscuous binding of this peptide to additional HLA-DR subtypes, as has been demonstrated for many other HLA-DR-restricted antigenic peptides, 16,19,[41][42][43] can be demonstrated or excluded only by analysis of a larger series of patients.…”

“…Even though the SEREX approach has considerably enlarged the pool of molecularly defined cancer testis antigens, 13 the ability of SEREX-defined antigen to induce T-cell responses has been demonstrated for only a few of them, namely NY-ESO-1 [14][15][16] and SSX2, [17][18][19][20] but not for SCP1, which has been shown to be the most frequently expressed CTA in a variety of neoplasms of different origin. [21][22][23][24] This holds particularly true for malignant lymphomas, in which other CTAs are rarely expressed.…”