Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy

• DOI: 10.1182/blood.2019004126
• Publication Date: 2020-03-11T01:59:54Z
• Authors: 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
• Keywords: Antimetabolites, Antineoplastic; Epstein-Barr Virus Infections; Herpesvirus 4, Human; 0303 health sciences; Apoptosis; Mice, SCID; Decitabine; Burkitt Lymphoma; Xenograft Model Antitumor Assays; Epigenesis, Genetic; 3. Good health; Mice; Viral Proteins; 03 medical and health sciences; Mice, Inbred NOD; Tumor Cells, Cultured; Animals; Humans; Immunotherapy; Cell Proliferation; T-Lymphocytes, Cytotoxic

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.