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Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy
Tanner Dalton1, Ekaterina Doubrovina2, Dmitry Pankov2
1Department of Biology, New York University, New York, NY.
Blood
|March 12, 2020
Summary
Decitabine reactivates immunogenic Epstein-Barr virus (EBV) antigens in EBV+ lymphomas, enhancing T-cell immunotherapy. This approach sensitizes tumors to EBV-specific cytotoxic T-cells, inhibiting growth in preclinical models.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Most Epstein-Barr virus (EBV)-positive lymphomas express latency I program, producing only poorly immunogenic EBNA1.
- This limited antigen expression allows tumors to evade immune responses, hindering T-cell immunotherapy effectiveness.
Purpose of the Study:
- To identify therapeutic strategies to overcome immune evasion in EBV+ lymphomas.
- To investigate decitabine's potential to re-sensitize EBV+ lymphomas to T-cell mediated lysis.
Main Methods:
- High-throughput screening to identify epigenetic modifiers.
- Treatment of EBV+ Burkitt lymphoma cell lines and xenografts with decitabine.
- Assessment of EBV antigen expression and sensitivity to EBV-specific cytotoxic T-cells (EBV-CTLs).
Main Results:
- Decitabine potently induces immunogenic EBV antigens (LMP1, EBNA2, EBNA3C) at low doses.
- Decitabine treatment sensitizes latency I EBV+ Burkitt lymphoma cells to EBV-CTL mediated lysis.
- Combination therapy of decitabine and EBV-CTLs inhibited tumor growth in preclinical xenograft models.
Conclusions:
- Decitabine overcomes latency restriction by inducing immunogenic EBV antigens.
- This epigenetic approach offers a novel strategy to enhance EBV-specific T-cell immunotherapy for EBV+ lymphomas.
