Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy
Tanner Dalton, Ekaterina Doubrovina, Dmitry Pankov, Raymond Reynolds, Hanna Scholze, Annamalai Selvakumar, Teresa Vizconde, Bhumesh Savalia, Vadim Dyomin, Christoph Weigel, Christopher C Oakes, Alicia Alonso, Olivier Elemento, Heng Pan, Jude M Phillip, Richard J O'Reilly, Benjamin E Gewurz, Ethel Cesarman, Lisa Giulino-Roth, Tanner Dalton, Ekaterina Doubrovina, Dmitry Pankov, Raymond Reynolds, Hanna Scholze, Annamalai Selvakumar, Teresa Vizconde, Bhumesh Savalia, Vadim Dyomin, Christoph Weigel, Christopher C Oakes, Alicia Alonso, Olivier Elemento, Heng Pan, Jude M Phillip, Richard J O'Reilly, Benjamin E Gewurz, Ethel Cesarman, Lisa Giulino-Roth
Abstract
Despite advances in T-cell immunotherapy against Epstein-Barr virus (EBV)-infected lymphomas that express the full EBV latency III program, a critical barrier has been that most EBV+ lymphomas express the latency I program, in which the single Epstein-Barr nuclear antigen (EBNA1) is produced. EBNA1 is poorly immunogenic, enabling tumors to evade immune responses. Using a high-throughput screen, we identified decitabine as a potent inducer of immunogenic EBV antigens, including LMP1, EBNA2, and EBNA3C. Induction occurs at low doses and persists after removal of decitabine. Decitabine treatment of latency I EBV+ Burkitt lymphoma (BL) sensitized cells to lysis by EBV-specific cytotoxic T cells (EBV-CTLs). In latency I BL xenografts, decitabine followed by EBV-CTLs results in T-cell homing to tumors and inhibition of tumor growth. Collectively, these results identify key epigenetic factors required for latency restriction and highlight a novel therapeutic approach to sensitize EBV+ lymphomas to immunotherapy.
Conflict of interest statement
Conflict-of-interest disclosure: L.G.-R. is a consultant for Janssen and ADC Therapeutics. D.P. was at Memorial Sloan Kettering Cancer Center while engaged in this project but is currently employed at GlaxoSmithKline. R.J.O. and E.D. received royalties following licensure of the EBV-specific T-cell bank by Atara Biotherapeutics and have subsequently received research support and consultant fees from Atara Biotherapeutics. The remaining authors declare no competing financial interests.
© 2020 by The American Society of Hematology.
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Source: PubMed