DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models.
DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models.
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DOI：
10.1038/s41467-018-04262-0
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发表时间：
2018-05-15
影响因子：
16.6
通讯作者：
Hirano N
中科院分区：
文献类型：
--
作者：
Kagoya Y;Nakatsugawa M;Saso K;Guo T;Anczurowski M;Wang CH;Butler MO;Arrowsmith CH;Hirano N
免疫T细胞疗法是一种很有前途的治疗癌症的方法。使用同种异体T细胞移植物将提高其适用性和多功能性，前提是控制固有的同种异体反应。T细胞活化由多种信号分子精细调节，这些信号分子由表观遗传机制转录控制。在这里，我们报告，抑制DOT 1 L，组蛋白H3-赖氨酸79甲基转移酶，增强同种异体T细胞反应。DOT 1 L抑制降低miR-181 a表达，这反过来增加ERK磷酸酶DUSP 6表达，并通过全面抑制T细胞活化诱导的基因表达改变来选择性改善低亲合力T细胞应答。抑制T细胞中DOT 1 L或DUSP 6过表达可减弱移植物抗宿主病的发展，同时在异种和同种异体过继免疫治疗模型中保留有效的抗肿瘤活性。这些结果表明，DOT 1 L抑制可以通过抑制过继免疫治疗中不需要的免疫反应来安全有效地使用同种异体抗肿瘤T细胞。使用同种异体T细胞移植物的连续性T细胞疗法是癌症中令人鼓舞的治疗方法，但诸如移植物抗宿主病等问题可能阻碍适用性。在这里，作者表明，DOT 1 L抑制或DUSP 6在T细胞中的过表达减弱了移植物抗宿主病，但在小鼠模型中保留了抗肿瘤活性。
Adoptive T-cell therapy is a promising therapeutic approach for cancer patients. The use of allogeneic T-cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. T-cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Here we report that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviates allogeneic T-cell responses. DOT1L inhibition reduces miR-181a expression, which in turn increases the ERK phosphatase DUSP6 expression and selectively ameliorates low-avidity T-cell responses through globally suppressing T-cell activation-induced gene expression alterations. The inhibition of DOT1L or DUSP6 overexpression in T cells attenuates the development of graft-versus-host disease, while retaining potent antitumor activity in xenogeneic and allogeneic adoptive immunotherapy models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in adoptive immunotherapy. Adoptive T cell therapy using an allogeneic T cell graft is an encouraging therapeutic approach in cancer, but issues such as graft-versus-host disease can hinder applicability. Here, the authors show that DOT1L inhibition or DUSP6 overexpression in T cells attenuates graft-versus-host disease but retains anti-tumour activity in mouse models.
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影响因子：
3.7
作者：
Butler MO;Imataki O;Yamashita Y;Tanaka M;Ansén S;Berezovskaya A;Metzler G;Milstein MI;Mooney MM;Murray AP;Mano H;Nadler LM;Hirano N
通讯作者：
Hirano N
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
8.8
作者：
Gandhi, M. K.;Wilkie, G. M.;Crawford, D. H.
通讯作者：
Crawford, D. H.
影响因子：
15.9
作者：
Kagoya, Yuki;Nakatsugawa, Munehide;Hirano, Naoto
通讯作者：
Hirano, Naoto
DUSP6/MKP-3对FGF信号传导的负反馈调节由ERK1/2驱动，并由ETS因子与DUSP6/MKP-3基因启动子内的保守位点结合介导。
DOI：
10.1042/bj20071512
发表时间：
2008-06-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Ekerot M;Stavridis MP;Delavaine L;Mitchell MP;Staples C;Owens DM;Keenan ID;Dickinson RJ;Storey KG;Keyse SM
通讯作者：
Keyse SM