Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion.
Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion.
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CDKN2aArf的表观遗传学控制保护肿瘤浸润性淋巴细胞免受代谢衰竭的影响。
DOI：
10.1158/0008-5472.can-20-0524
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发表时间：
2020-11-01
期刊：
影响因子：
11.2
通讯作者：
Tackett AJ
中科院分区：
文献类型：
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作者：
Koss B;Shields BD;Taylor EM;Storey AJ;Byrum SD;Gies AJ;Washam CL;Choudhury SR;Hyun Ahn J;Uryu H;Williams JB;Krager KJ;Chiang TC;Mackintosh SG;Edmondson RD;Aykin-Burns N;Gajewski TF;Wang GG;Tackett AJ
癌症中的T细胞耗竭与不良的临床结果有关，其中证据表明T细胞代谢变化先于功能耗竭。肿瘤浸润淋巴细胞（TIL）和癌细胞之间对代谢资源的直接竞争往往使T细胞功能失调。环境应激在TIL内产生由组蛋白甲基转移酶EZH2的损失引起的表观基因组重塑事件。在这里，我们报告了一个表观遗传机制，有助于发展的代谢衰竭的TIL。多漫画方法揭示了Cdkn2a. Arf介导的p53非依赖性机制，通过该机制EZH2抑制导致线粒体功能障碍和由此产生的耗竭。重编程T细胞以表达功能获得性EZH2突变体导致T细胞在体外和体内抑制肿瘤生长的能力增强。我们的数据表明，在细胞疗法的背景下操作T细胞EZH2可以产生能够耐受苛刻的肿瘤代谢环境和附带的药理学损伤的淋巴细胞。
T cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Environmental stress produces epigenome remodeling events within TIL resulting from loss of the histone methyltransferase EZH2. Here we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TIL. A multi-comics approach revealed a Cdkn2a.Arf-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth in vitro and in vivo. Our data suggest that manipulation of T cell EZH2 within the context of cellular therapies may yield lymphocytes that are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults.