Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to viral directed immunotherapy.

Despite advances in T-cell immunotherapy against 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 sensitized cells to lysis by EBV-specific cytotoxic T-cells (EBV-CTLs). In latency I Burkitt lymphoma 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.