Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma.
Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma.
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DOI：
10.1126/sciadv.abo8043
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发表时间：
2022-10-07
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
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晚期尿路上皮癌（UCa）患者的长期生存是有限的，因为先天性耐药治疗。我们确定组蛋白甲基转移酶EZH2的表达升高是侵袭性UCa的标志，并假设通过小分子催化抑制剂抑制EZH2可能在UCa中具有抗肿瘤作用。在此，在致癌物诱导的小鼠膀胱癌模型中，观察到EZH2抑制后肿瘤进展的减少和免疫浸润的增加。用EZH2i治疗小鼠导致尿路上皮中MHC II类表达增加，并且可以激活浸润性T细胞。出乎意料的是，我们发现缺乏完整的适应性免疫系统完全消除了EZH2催化抑制诱导的抗肿瘤作用。这些发现表明，免疫逃避是UCa模型中EZH2催化抑制治疗功效的唯一重要决定因素。膀胱癌中的EZH2抑制仅通过抑制适应性免疫应答来强烈降低肿瘤进展。
The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model. EZH2 inhibition in bladder cancer strongly reduces tumor progression only through suppression of an adaptive immune response.
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