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NY-ESO-1 encodes DRB1*0401-restricted epitopes recognized by melanoma-reactive CD4+ T cells
H M Zarour1, W J Storkus, V Brusic
1Department of Medicine and Melanoma Center, University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA. zarourhm@msx.upmc.edu
Abstract:
The NY-ESO-1 gene is expressed by a range of human tumors and encodes HLA-A2-restricted melanoma peptides recognized by CD8+ CTLs. Here we report that the NY-ESO-1 gene also encodes two overlapping, but non-cross-reactive, HLA-DRB1*0401-presented peptides that are recognized by CD4+ T cells. The NY-ESO-1(119-143) peptide was able to induce specific CD4+ T cells in vitro from both an HLA-DRB1*0401+ normal donor and an HLA-DRB1*0401+ patient with melanoma. Bulk and cloned CD4+ T cells produced IFN-gamma specifically in response to, and also lysed, T2.DR4 cells pulsed with peptide NY-ESO-1(119-143) and the autologous tumor cell line, but not a DRB1*0401+ melanoma cell line that does not express NY-ESO-1. Interestingly, the NY-ESO119-143 peptide contains two overlapping putative "core" epitopes recognized by non-cross-reactive anti-NY-ESO-1(119-143) CD4+ T-cell clones. Taken together, these data support the use of this novel DR4-restricted tumor peptide, NY-ESO-1(119-143), or its two "sub-epitopes" in immunotherapeutic trials designed to generate or enhance specific CD4+ T-cell responses against tumors expressing NY-ESO-1 in vivo.
Insights
The NY-ESO-1 gene yields peptides recognized by CD4+ T cells, including a novel DR4-restricted peptide NY-ESO-1(119-143). This peptide and its sub-epitopes show promise for cancer immunotherapy by enhancing CD4+ T-cell responses.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The NY-ESO-1 gene is a tumor antigen expressed in various human cancers.
- NY-ESO-1 encodes peptides recognized by CD8+ cytotoxic T lymphocytes (CTLs) in an HLA-A2-restricted manner.
- The potential for NY-ESO-1 to be recognized by CD4+ T cells remains less explored.
Purpose of the Study:
- To identify and characterize novel NY-ESO-1-derived peptides presented by HLA-DRB1*0401.
- To investigate the immunogenicity and T-cell response to these novel peptides.
- To evaluate the potential of these peptides in cancer immunotherapy.
Main Methods:
- Peptide identification and synthesis.
- In vitro induction of CD4+ T cells from healthy donors and melanoma patients.
- Assays for T-cell proliferation, cytokine production (IFN-gamma), and cytotoxicity.
- Analysis of T-cell recognition of peptide-pulsed cells and tumor cell lines.
Main Results:
- The NY-ESO-1 gene encodes two overlapping, non-cross-reactive peptides presented by HLA-DRB1*0401.
- The peptide NY-ESO-1(119-143) induced specific CD4+ T cells in vitro.
- Induced CD4+ T cells produced IFN-gamma and lysed target cells presenting the NY-ESO-1(119-143) peptide.
- The NY-ESO-1(119-143) peptide contains two distinct core epitopes recognized by non-cross-reactive CD4+ T-cell clones.
Conclusions:
- The novel DR4-restricted tumor peptide NY-ESO-1(119-143) is recognized by CD4+ T cells.
- This peptide and its sub-epitopes can elicit specific CD4+ T-cell responses.
- NY-ESO-1(119-143) and its sub-epitopes are potential candidates for cancer immunotherapeutic strategies targeting NY-ESO-1-expressing tumors.