CD4⁺T cell recognition of MHC class II-restricted epitopes from NY-ESO-1 presented by a prevalent HLA DP4 allele: Association with NY-ESO-1 antibody production

Abstract

NY-ESO-1 is a tumor-specific shared antigen with distinctive immunogenicity. Both CD8 ؉ T cells and class-switched Ab responses have been detected from patients with cancer. In this study, a CD4 ؉ T cell line was generated from peripheral blood mononuclear cells of a melanoma patient and was shown to recognize NY-ESO-1 peptides presented by HLA-DP4, a dominant MHC class II allele expressed in 43-70% of Caucasians. The ESO p157-170 peptide containing the core region of DP4-restricted T cell epitope was present in a number of tumor cell lines tested and found to be recognized by both CD4 ؉ T cells as well as HLA-A2-restricted CD8 ؉ T cells. Thus, the ESO p157-170 epitope represents a potential candidate for cancer vaccines aimed at generating both CD4 ؉ and CD8 ؉ T cell responses. More importantly, 16 of 17 melanoma patients who developed Ab against NY-ESO-1 were found to be HLA-DP4-positive. CD4 ؉ T cells specific for the NY-ESO-1 epitopes were generated from 5 of 6 melanoma patients with NY-ESO-1 Ab. In contrast, no specific DP4-restricted T cells were generated from two patients without detectable NY-ESO-1 Ab. These results suggested that NY-ESO-1-specific DP4-restricted CD4 ؉ T cells were closely associated with NY-ESO-1 Ab observed in melanoma patients and might play an important role in providing help for activating B cells for NY-ESO-1-specific Ab production.A number of studies suggest that tumor-reactive T cells play an important role in mediating tumor regression. The molecular basis of T cell-mediated antitumor immunity has been elucidated by the identification of a number of tumor antigens recognized by CD8 ϩ T cells (1, 2). These MHC class I-restricted tumor antigens can be divided into several categories. The tissue-specific differentiation antigens, which include MART-1 (3), TRP-1͞gp75 (4), TRP-2 (5), and gp100 (6) are expressed in melanoma as well as normal melanocytes. Tumor-specific shared antigens such as MAGE-1 (7) and NY-ESO-1 (8, 9) are expressed in a wide variety of tumors such as breast cancer and lung cancer. The expression of these products is limited in cancer cells with the exception of normal testis. Tumor-specific unique or mutated antigens such as ␤-catenin (10) also have been described. Among these antigens, NY-ESO-1 is of particular interest because both cytotoxic T lymphocyte and Ab responses have been shown to react with this antigen (9, 11). NY-ESO-1 encodes two gene products recognized by CD8 ϩ T cell clones (9). In addition, high titers of Ab were detected from about 50% of patients with NY-ESO-1-positive tumor (12). Because of its strict tumor-specific expression pattern (8), NY-ESO-1 is potentially an important immune target for the development of immunotherapy for a variety of cancer types.Increasing evidence from both human and animal studies has indicated that CD4 ϩ T cells play a central role in initiating and maintaining host immune responses against cancer (2, 13). The observation that high titers of NY-ESO-1 antibodies were present in a high proportion of patients sugg...

Adenovirus hexon T-cell epitope is recognized by most adults and is restricted by HLA DP4, the most common class II allele

“…Examples include the tumor antigens NY-ESO-1 and MAGE 3 and viral antigens from rabies and hepatitis B virus. [13][14][15][16] The identification of HLA DP4 epitopes from viral and tumor antigens will be valuable tools because these CD4 T-cell epitopes can be recognized by a majority of the general population. For instance, dendritic cells loaded with the MAGE 3 HLA DP4 peptide have recently been shown to induce T-helper cell responses in a majority of patients with metastatic melanoma.…”

Primary Human Lymphocytes Transduced with NY-ESO-1 Antigen-Specific TCR Genes Recognize and Kill Diverse Human Tumor Cell Lines

“…Additionally, it may be possible to up-regulate NY-ESO-1 expression in cancer patients by treatment with drugs that induce DNA demethylation (38,39). Finally, we have identified MHC class II-restricted NY-ESO-1 TCR epitopes (22,40,41), and we are currently attempting to simultaneously engineer a population of T cells with both class Iand class II-restricted TCRs. …”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Abundant data indicate that 'shared' melanocyte lineage antigens, such as tyrosinase 38 , can be recognized by T cells in patients with melanoma, particularly following investigational vaccinations [39][40][41] . Larger-scale analyses are needed to understand the full repertoire of shared and tumour-specific epitopes that can be recognized in melanomas, even in untreated patients.…”