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MAGE-C2-Specific TCRs Combined with Epigenetic Drug-Enhanced Antigenicity Yield Robust and Tumor-Selective T Cell Responses.

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Kunert, Andre van Brakel, Mandy van Steenbergen-Langeveld, Sabine da Silva, Marvin Coulie, Pierre G. [UCL] Debets, Reno

Adoptive T cell therapy has shown significant clinical success for patients with advanced melanoma and other tumors. Further development of T cell therapy requires improved strategies to select effective, yet nonself-reactive, TCRs. In this study, we isolated 10 TCR sequences against four MAGE-C2 (MC2) epitopes from melanoma patients who showed clinical responses following vaccination that were accompanied by significant frequencies of anti-MC2 CD8 T cells in blood and tumor without apparent side effects. We introduced these TCRs into T cells, pretreated tumor cells of different histological origins with the epigenetic drugs azacytidine and valproate, and tested tumor and self-reactivities of these TCRs. Pretreatment of tumor cells upregulated MC2 gene expression and enhanced recognition by T cells. In contrast, a panel of normal cell types did not express MC2 mRNA, and similar pretreatment did not result in recognition by MC2-directed T cells. Interestingly, the expression levels of MC2, but not those of CD80, CD86, or programmed death-ligand 1 or 2, correlated with T cell responsiveness. One of the tested TCRs consistently recognized pretreated MC2(+) cell lines from melanoma, head and neck, bladder, and triple-negative breast cancers but showed no response to MHC-eluted peptides or peptides highly similar to MC2. We conclude that targeting MC2 Ag, combined with epigenetic drug-enhanced antigenicity, allows for significant and tumor-selective T cell responses.

Document type Article de périodique (Journal article) – Article de recherche
Publication date 2016
Language Anglais
Journal information "Journal of Immunology" - Vol. 197, no.6, p. 2541-2552 (2016)
Peer reviewed yes
Publisher American Association of Immunologists
issn 0022-1767
e-issn 1550-6606
Publication status Publié
Affiliation UCL - SSS/DDUV - Institut de Duve
Links
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Bibliographic reference Kunert, Andre ; van Brakel, Mandy ; van Steenbergen-Langeveld, Sabine ; da Silva, Marvin ; Coulie, Pierre G. ; et. al. MAGE-C2-Specific TCRs Combined with Epigenetic Drug-Enhanced Antigenicity Yield Robust and Tumor-Selective T Cell Responses.. In: Journal of Immunology, Vol. 197, no.6, p. 2541-2552 (2016)
Permanent URL http://hdl.handle.net/2078.1/182272