DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets

DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets

Cancer testis antigens (CTAs) can be expressed in tumors, whereas expression is silenced in normal tissue except for the immune-privileged testis. This quasi-tumor-restricted expression makes CTAs attractive targets for T cell receptor (TCR) gene therapy. However, CTA-specific TCR gene therapy is on...

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Main Authors: Marije A.J. de Rooij, Miranda H. Meeuwsen, Anne K. Wouters, Dennis F.G. Remst, Renate S. Hagedoorn, Dirk M. van der Steen, Els M.E. Verdegaal, Tassilo L.A. Wachsmann, J.H. Frederik Falkenburg, Mirjam H.M. Heemskerk
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Molecular Therapy: Oncology
Subjects:
MT: Regular Issue
CD8+ T cell
TCR
DAC
MAGE
DNA-demethylation
Online Access:http://www.sciencedirect.com/science/article/pii/S2950329925000876
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Summary:Cancer testis antigens (CTAs) can be expressed in tumors, whereas expression is silenced in normal tissue except for the immune-privileged testis. This quasi-tumor-restricted expression makes CTAs attractive targets for T cell receptor (TCR) gene therapy. However, CTA-specific TCR gene therapy is only applicable for tumors with substantial and homogeneous CTA expression. To increase the number of patients eligible for CTA-specific TCR gene therapy, CTA expression can be upregulated with DNA-demethylating agents like 5-aza-2′-deoxycytidine (DAC). Here, we studied the effect of DAC on the recognition of a wide range of tumor cells by TCR-engineered T cells specific for the CTAs MAGE-A1, MAGE-A3/A6, or MAGE-A9. DAC treatment strongly increased MAGE expression in most tumor cell lines tested and strongly induced or improved recognition by MAGE-specific TCR-engineered T cells. However, MAGE upregulation was not limited to tumor cells but also occurred in healthy cells, resulting in MAGE-specific T cell reactivity against proliferating T and B cells. Overall, these results underscore the potential of DAC treatment to induce MAGE expression in tumor cells and to increase their sensitivity for MAGE-specific T cell therapy. However, DAC treatment can potentially result in on-target off-tumor reactivity, warranting careful consideration when using DAC as sensitizing strategy prior to adoptive transfer of CTA-specific T cells.
ISSN:2950-3299

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