Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Mol Immunol. 2020 Mar;119:35-45. doi: 10.1016/j.molimm.2020.01.006. Epub 2020 Jan 18.
Loss of CD58 is a common mechanism for tumor immune evasion in lymphoid malignancies. CD58 loss is known to occur due to both genetic and non-genetic causes; therefore, we hypothesized that restoring CD58 expression in lymphoma cells may be an effective treatment approach. To explore the potential for restoring CD58 expression, we first screened 11 B-cell lymphoma lines and found that 3 had decreased CD58 expression. Among these, CD58 was genetically damaged in two lines but not in the third line. Using the cell line with downregulated CD58 without a genetic abnormality, we performed epigenetic library screening and found that two EZH2 inhibitors, EPZ6438 and GSK126, specifically enhanced CD58 expression. By examining the effect of three EZH2 inhibitors with different selectivity profiles in different B-cell lines, EZH2 inhibition was shown to have a common activity in upregulating CD58 expression. Restoring the expression of CD58 in lymphoma cells using an EZH2 inhibitor was shown to enhance interferon-γ production of T and NK cells against lymphoma cells. H3K27 was shown to be highly trimethylated in the CD58 promoter region, and EZH2 inhibition induced its demethylation and activated transcription of the CD58 gene. These results indicated that EZH2 is involved in the epigenetic silencing of CD58 in lymphoma cells as a mechanism for tumor immune escape, and EZH2 inhibitors are able to restore epigenetically suppressed CD58 expression. Our findings provide a molecular basis for the combination of an EZH2 inhibitor and immunotherapy for lymphoma treatment.
CD58 的丢失是淋巴恶性肿瘤肿瘤免疫逃逸的常见机制。已知 CD58 的丢失既可以由遗传因素引起，也可以由非遗传因素引起；因此，我们假设在淋巴瘤细胞中恢复 CD58 的表达可能是一种有效的治疗方法。为了探索恢复 CD58 表达的潜力，我们首先筛选了 11 种 B 细胞淋巴瘤细胞系，发现其中 3 种细胞系的 CD58 表达降低。在这 3 种细胞系中，有 2 种细胞系的 CD58 基因受损，而另 1 种细胞系则没有基因异常。我们利用 CD58 表达下调但没有遗传异常的细胞系进行表观遗传文库筛选，发现两种 EZH2 抑制剂（EPZ6438 和 GSK126）特异性地上调 CD58 的表达。通过研究三种具有不同选择性特征的 EZH2 抑制剂在不同 B 细胞系中的作用，我们发现 EZH2 抑制作用具有共同的上调 CD58 表达的活性。用 EZH2 抑制剂恢复淋巴瘤细胞中 CD58 的表达，可增强 T 和 NK 细胞对淋巴瘤细胞的干扰素-γ产生。CD58 启动子区域的 H3K27 高度三甲基化，EZH2 抑制作用诱导其去甲基化并激活 CD58 基因的转录。这些结果表明，EZH2 作为肿瘤免疫逃逸的一种机制，参与了淋巴瘤细胞中 CD58 的表观遗传沉默，EZH2 抑制剂能够恢复表观遗传抑制的 CD58 表达。我们的研究结果为 EZH2 抑制剂与免疫疗法联合治疗淋巴瘤提供了分子基础。
