LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade.
LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade.
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DOI：
10.1038/s41467-021-27179-7
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发表时间：
2021-11-24
影响因子：
16.6
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Liu Y;Debo B;Li M;Shi Z;Sheng W;Shi Y
耗尽的CD8+T细胞是免疫检查点阻断治疗的关键靶点，其无效的恢复限制了一些癌症患者的持久受益。在这里，我们证明了组蛋白去甲基酶LSD1在祖细胞耗竭的CD8+T细胞中执行表观遗传程序，以对抗TCF1介导的祖细胞维持并促进末端分化。因此，针对LSD1的遗传扰动或小分子增加了祖细胞耗竭CD8+T细胞的持久性，这为增殖转化为具有肿瘤杀伤细胞毒性的较大的终末耗尽T细胞提供了持续的来源，从而导致对抗PD1治疗的有效和持久的反应。总而言之，我们的发现为调节T细胞耗竭的表观遗传学机制提供了重要的见解，并对持久的免疫治疗具有重要意义。染色质景观的动态变化影响CD8+T细胞在慢性感染和癌症中的表型和功能。在这里，作者证明了靶向组蛋白去甲基酶LSD1增加了祖细胞耗尽CD8+T细胞的持久性，改善了临床前癌症模型对免疫检查点阻断的反应。
Exhausted CD8+ T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8+ T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8+ T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy. Dynamic changes in chromatin landscape affect CD8+ T cell phenotype and function in chronic infections and cancer. Here the authors show that targeting the histone demethylase LSD1 increases the persistence of progenitor exhausted CD8+ T cells, improving response to immune checkpoint blockade in preclinical cancer models.
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DOI：
10.1093/biostatistics/kxr054
发表时间：
2012-04
期刊：
Biostatistics (Oxford, England)
影响因子：
--
作者：
Hansen KD;Irizarry RA;Wu Z
通讯作者：
Wu Z
影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
7.2
作者：
Carmona, Santiago J.;Siddiqui, Imran;Gfeller, David
通讯作者：
Gfeller, David
影响因子：
7.7
作者：
Kerenyi MA;Shao Z;Hsu YJ;Guo G;Luc S;O'Brien K;Fujiwara Y;Peng C;Nguyen M;Orkin SH
通讯作者：
Orkin SH