Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition
Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition
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DOI：
10.1158/2159-8290.cd-18-1090
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发表时间：
2019-04-01
期刊：
影响因子：
28.2
通讯作者：
Steidl, Christian
中科院分区：
文献类型：
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作者：
Ennishi, Daisuke;Takata, Katsuyoshi;Steidl, Christian
我们对347例弥漫性大B细胞淋巴瘤（DLBCL）患者进行了基因组学、转录组学和免疫表型研究，以揭示获得性MHC表达缺陷的分子基础。低MHC-II表达定义肿瘤起源于与较差预后相关的生发中心（GC）的中心母细胞丰富的暗区。MHC-II缺陷型肿瘤的特征是体细胞获得性基因突变降低MHC-II表达和肿瘤浸润淋巴细胞数量减少。特别是，我们证明了EZH 2突变在MHC-I和MHC-II阴性原发性淋巴瘤中的高度富集，并观察到表达突变EZH 2（Y）的鼠淋巴瘤模型中MHC表达和T细胞浸润减少（641）。具有临床相关性的是，EZH 2抑制剂显著恢复了EZH 2突变的人DLBCL细胞系中的MHC表达。因此，我们的研究结果表明，在GC衍生的淋巴瘤的获得性免疫逃逸的肿瘤进展模型，并铺平了道路的发展互补的治疗方法相结合的免疫治疗与表观遗传reprogramming.SIGNIFICANCE：我们展示了如何MHC缺陷的淋巴肿瘤在细胞的起源特定的背景下演变。具体而言，EZH 2突变被鉴定为获得性MHC缺陷的遗传机制。EZH 2抑制剂对MHC表达的典型恢复为将免疫疗法与表观遗传重编程相结合以增强肿瘤识别和消除的协同疗法提供了理论基础。
We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II-deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I- and MHC-II-negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2(Y)(641). Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming.SIGNIFICANCE: We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin-specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination.