Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.
Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.
复制标题
DOI：
10.1038/nature15520
复制
发表时间：
2015-11-12
期刊：
影响因子：
64.8
通讯作者：
Zou W
中科院分区：
文献类型：
--
作者：
Peng D;Kryczek I;Nagarsheth N;Zhao L;Wei S;Wang W;Sun Y;Zhao E;Vatan L;Szeliga W;Kotarski J;Tarkowski R;Dou Y;Cho K;Hensley-Alford S;Munkarah A;Liu R;Zou W
表观遗传沉默（包括组蛋白修饰和 DNA 甲基化）是一种重要的致瘤机制，然而，其在癌症免疫病理学和免疫治疗中的作用却知之甚少。使用卵巢癌作为我们的模型，我们发现zeste同源物增强子2（EZH2）介导的组蛋白H3赖氨酸27三甲基化（H3K27me3）和DNA甲基转移酶（DNMT）1介导的DNA甲基化抑制Th1型趋化因子CXCL9和CXCL10的肿瘤产生，并随后确定效应T细胞向肿瘤微环境的运输。表观遗传调节剂治疗可消除抑制并增加效应 T 细胞肿瘤浸润，减缓肿瘤进展，并提高荷瘤小鼠中 PD-L1 (B7-H1) 检查点阻断和过继 T 细胞输注的治疗效果。此外，肿瘤 EZH2 和 DNMT1 与肿瘤浸润 CD8+ T 细胞和患者预后呈负相关。因此，Th1型趋化因子的表观遗传沉默是一种新型的肿瘤免疫逃避机制。选择性表观遗传重编程改变癌症中的 T 细胞景观，并可能增强癌症治疗的临床疗效。
Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism However, its role in cancer immunopathology and immunotherapy is poorly understood. Using ovarian cancers as our model, we found that enhancer of zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase (DNMT) 1-mediated DNA methylation repress the tumor production of Th1-type chemokines CXCL9 and CXCL10, and subsequently determine effector T cell trafficking to the tumor microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T cell tumor infiltration, slows down tumor progression, and improves therapeutic efficacy of PD-L1 (B7-H1) checkpoint blockade and adoptive T cell transfusion in tumor bearing mice. Moreover, tumor EZH2 and DNMT1 are negatively associated with tumor infiltrating CD8+ T cells and patient outcome. Thus, epigenetic silencing of Th1-type chemokine is a novel tumor immune evasion mechanism. Selective epigenetic reprogramming alters T cell landscape in cancer and may enhance clinical efficacy of cancer therapy.