Epigenetic reprogramming sensitizes immunologically silent ...

LYMPHOID NEOPLASIA| MAY 21, 2020

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

Blood (2020) 135 (21): 1870–1881.

https://doi.org/10.1182/blood.2019004126

Key Points

A high-throughput screen identified hypomethylating agents as inducers of latency III viral antigens in latency I EBV+ BL.

Induction of latency III antigens in BL sensitizes resistant tumors to T-cell–mediated lysis with EBV-specific cytotoxic T lymphocytes.

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.

Subjects:

Immunobiology and Immunotherapy, Lymphoid Neoplasia

Topics:

antigens, decitabine, herpesvirus 4, human, immunotherapy, lymphoma, neoplasms, t-lymphocytes, epigenetics, transplantation, heterologous

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