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Epigenetic changes in tumor Fas levels determine immune escape and response to therapy
Heather L Maecker1, Zhong Yun, Holden T Maecker
1Department of Radiation Oncology, Stanford University Medical Center, CCSR South, 269 Campus Drive, Stanford, California 94305, USA. hmaecker@gene.com
Abstract:
Epigenetic regulation of gene expression significantly influences cell growth and differentiation. Here we show that epigenetic silencing of Fas determines tumor growth in vivo and apoptotic sensitivity in vitro. In established tumors with epigenetically repressed Fas, restoration of Fas activity either by transfection of fas or treatment with Trichostatin A (TSA), an inhibitor of histone deacetylase, suppresses tumor growth and restores chemosensitivity. The TSA-dependent chemosensitivity and tumor growth control require both tumor Fas and the host NK (natural killer) cell functions. This work demonstrates the importance of epigenetic modification of Fas in tumor progression and immune evasion, and emphasizes the essential interplay between Fas and innate immunity in the control of chemoresistant tumors.
Insights
Epigenetic silencing of Fas promotes tumor growth and resistance to chemotherapy. Restoring Fas activity, through gene therapy or HDAC inhibitors like TSA, suppresses tumors and enhances chemosensitivity by engaging NK cells.
Area of Science:
- Molecular Biology
- Immunology
- Cancer Research
Background:
- Epigenetic regulation controls gene expression impacting cell growth and differentiation.
- Fas, a key mediator of apoptosis, can be epigenetically silenced in tumors.
- Tumor progression and immune evasion are linked to epigenetic modifications.
Purpose of the Study:
- To investigate the role of epigenetic silencing of Fas in tumor growth and chemosensitivity.
- To determine if restoring Fas activity can reverse tumor progression and chemoresistance.
- To elucidate the involvement of host immune cells in Fas-mediated tumor control.
Main Methods:
- Studied epigenetic silencing of Fas in tumor models.
- Restored Fas activity via gene transfection and Trichostatin A (TSA) treatment.
- Assessed tumor growth, apoptotic sensitivity, and chemosensitivity.
- Investigated the role of tumor Fas and host NK cells in therapeutic responses.
Main Results:
- Epigenetic silencing of Fas was found to drive tumor growth and reduce apoptotic sensitivity.
- Restoration of Fas activity, using either Fas transfection or TSA, suppressed tumor growth.
- TSA treatment restored chemosensitivity, dependent on both tumor Fas and host NK cell function.
- Demonstrated that innate immunity, specifically NK cells, is crucial for controlling chemoresistant tumors.
Conclusions:
- Epigenetic modification of Fas is critical for tumor progression and immune evasion.
- Restoring Fas activity presents a therapeutic strategy for chemoresistant tumors.
- The interplay between Fas signaling and innate immunity is essential for effective tumor control.