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...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-09-01
|
| Series: | Molecular Therapy: Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329925000876 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849247198988992512 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Marije A.J. de Rooij |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-898a1ed0dba945e2b07f3b91a668f31c |
| institution | Kabale University |
| issn | 2950-3299 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-898a1ed0dba945e2b07f3b91a668f31c2025-08-20T03:58:18ZengElsevierMolecular Therapy: Oncology2950-32992025-09-0133320101810.1016/j.omton.2025.201018DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsetsMarije A.J. de Rooij0Miranda H. Meeuwsen1Anne K. Wouters2Dennis F.G. Remst3Renate S. Hagedoorn4Dirk M. van der Steen5Els M.E. Verdegaal6Tassilo L.A. Wachsmann7J.H. Frederik Falkenburg8Mirjam H.M. Heemskerk9Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden 2333ZA, the NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands; Corresponding author: Mirjam H.M. Heemskerk, Department of Hematology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.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.http://www.sciencedirect.com/science/article/pii/S2950329925000876MT: Regular IssueCD8+ T cellTCRDACMAGEDNA-demethylation |
| spellingShingle | 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 DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets Molecular Therapy: Oncology MT: Regular Issue CD8+ T cell TCR DAC MAGE DNA-demethylation |
| title | DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets |
| title_full | DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets |
| title_fullStr | DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets |
| title_full_unstemmed | DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets |
| title_short | DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets |
| title_sort | dna demethylation by dac induces mage expression and mage specific t cell reactivity against tumors but also healthy cell subsets |
| topic | MT: Regular Issue CD8+ T cell TCR DAC MAGE DNA-demethylation |
| url | http://www.sciencedirect.com/science/article/pii/S2950329925000876 |
| work_keys_str_mv | AT marijeajderooij dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT mirandahmeeuwsen dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT annekwouters dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT dennisfgremst dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT renateshagedoorn dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT dirkmvandersteen dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT elsmeverdegaal dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT tassilolawachsmann dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT jhfrederikfalkenburg dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets AT mirjamhmheemskerk dnademethylationbydacinducesmageexpressionandmagespecifictcellreactivityagainsttumorsbutalsohealthycellsubsets |