Department of Biology, New York University, New York, NY.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
Blood. 2020 May 21;135(21):1870-1881. doi: 10.1182/blood.2019004126.
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.
尽管在针对表达完整 EBV 潜伏期 III 程序的 EBV 感染淋巴瘤的 T 细胞免疫疗法方面取得了进展，但一个关键的障碍是大多数 EBV+淋巴瘤表达潜伏期 I 程序，其中仅产生单个 EBV 核抗原 (EBNA1)。EBNA1 的免疫原性很差，使肿瘤能够逃避免疫反应。我们使用高通量筛选发现地西他滨是一种有效的免疫原性 EBV 抗原诱导剂，包括 LMP1、EBNA2 和 EBNA3C。诱导作用发生在低剂量下，并且在去除地西他滨后仍然存在。地西他滨治疗潜伏期 I EBV+伯基特淋巴瘤 (BL) 可使细胞对 EBV 特异性细胞毒性 T 细胞 (EBV-CTL) 的裂解敏感。在潜伏期 I BL 异种移植物中，地西他滨加 EBV-CTL 导致 T 细胞归巢到肿瘤并抑制肿瘤生长。总之，这些结果确定了限制潜伏期所必需的关键表观遗传因素，并强调了一种使 EBV+淋巴瘤对免疫疗法敏感的新治疗方法。
