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Identification of new antigenic peptide presented by HLA-Cw7 and encoded by several MAGE genes using dendritic cells
Karine Breckpot1, Carlo Heirman, Catherine De Greef
1Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Brussels, Belgium.
Abstract:
Antigens encoded by MAGE genes are of particular interest for cancer immunotherapy because they are tumor specific and shared by tumors of different histological types. Several clinical trials are in progress with MAGE peptides, proteins, recombinant poxviruses, and dendritic cells (DC) pulsed with peptides or proteins. The use of gene-modified DC would offer the major advantage of a long-lasting expression of the transgene and a large array of antigenic peptides that fit into the different HLA molecules of the patient. In this study, we tested the ability of gene-modified DC to prime rare Ag-specific T cells, and we identified a new antigenic peptide of clinical interest. CD8(+) T lymphocytes from an individual without cancer were stimulated with monocyte-derived DC, which were infected with a second-generation lentiviral vector encoding MAGE-3. A CTL clone was isolated that recognized peptide EGDCAPEEK presented by HLA-Cw7 molecules, which are expressed by >40% of Caucasians. Interestingly, this new tumor-specific antigenic peptide corresponds to position 212-220 of MAGE-2, -3, -6, and -12. HLA-Cw7 tumor cell lines expressing one of these MAGE genes were lysed by the CTL, indicating that the peptide is efficiently processed in tumor cells and can therefore be used as target for antitumoral vaccination. The risk of tumor escape due to appearance of Ag-loss variants should be reduced by the fact that the peptide is encoded by several MAGE genes.
Insights
Gene-modified dendritic cells (DC) can stimulate rare T cells. Researchers identified a new MAGE tumor antigen peptide (EGDCAPEEK) presented by HLA-Cw7, offering a promising target for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- MAGE antigens are crucial for cancer immunotherapy due to their tumor specificity.
- Current trials utilize MAGE peptides, proteins, and modified dendritic cells (DC).
- Gene-modified DC offer sustained transgene expression and diverse antigenic peptide presentation for various HLA types.
Purpose of the Study:
- To evaluate gene-modified DC's capacity to prime rare antigen-specific T cells.
- To identify novel antigenic peptides with clinical relevance for cancer vaccination.
Main Methods:
- Monocyte-derived DC were engineered using a lentiviral vector encoding MAGE-3.
- CD8(+) T lymphocytes from healthy donors were stimulated with modified DC.
- Cytotoxic T Lymphocyte (CTL) clones were isolated and characterized.
Main Results:
- A novel CTL clone recognized the MAGE peptide EGDCAPEEK presented by HLA-Cw7.
- This peptide is derived from MAGE-2, -3, -6, and -12, common in Caucasian populations (>40%).
- Engineered HLA-Cw7 tumor cell lines expressing MAGE genes were effectively lysed by the CTL clone.
Conclusions:
- Gene-modified DC can effectively prime rare T cells against tumor antigens.
- The identified MAGE peptide (EGDCAPEEK) is a promising candidate for antitumoral vaccination due to its broad MAGE gene origin and HLA-Cw7 presentation.
- Targeting this peptide may reduce tumor escape via antigen loss variants.
