MEK inhibition reprograms CD8(+) T lymphocytes into memory stem cells with potent antitumor effects.
MEK inhibition reprograms CD8(+) T lymphocytes into memory stem cells with potent antitumor effects.
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DOI：
10.1038/s41590-020-00818-9
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发表时间：
2021-01
影响因子：
30.5
通讯作者：
Khleif, Samir N.
中科院分区：
文献类型：
--
作者：
Verma, Vivek;Jafarzadeh, Nazli;Boi, Shannon;Kundu, Subhadip;Jiang, Zhinuo;Fan, Yiping;Lopez, Jose;Nandre, Rahul;Zeng, Peng;Alolaqi, Fatmah;Ahmad, Shamim;Gaur, Pankaj;Barry, Simon T.;Valge-Archer, Viia E.;Smith, Paul D.;Banchereau, Jacques;Mkrtichyan, Mikayel;Youngblood, Benjamin;Rodriguez, Paulo C.;Gupta, Seema;Khleif, Samir N.
再生干细胞样记忆（TSCM）CD 8 + T细胞持续时间更长，产生更强的效应功能。我们发现，MEK 1/2抑制（MEKi）诱导TSCM具有幼稚表型，具有自我更新能力，增强的多能性和增殖能力。这是通过延迟细胞分裂和增强线粒体生物合成和脂肪酸氧化来实现的，而不影响T细胞受体介导的活化。DNA甲基化分析显示，MEKi诱导的TSCM细胞表现出可塑性和基因座特异性的配置文件类似于真正的TSCM从健康供体分离，中间的特点相比，幼稚和中央记忆T细胞。离体，MEKi处理的CD 8 + T细胞的抗原再激发显示出更强的回忆应答。这种策略产生的T细胞对于过继性细胞治疗具有更高的功效。此外，MEKi治疗荷瘤小鼠也显示出强烈的免疫介导的抗肿瘤作用。总之，我们表明，MEKi导致CD 8 + T细胞重编程为TSCM，作为一个水库的效应T细胞具有强大的治疗特性。
Regenerative stem cell–like memory (TSCM) CD8+ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces TSCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced TSCM cells exhibited plasticity and loci-specific profiles similar to bona fide TSCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8+ T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8+ T cell reprogramming into TSCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.
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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：
32.4
作者：
Herndler-Brandstetter D;Ishigame H;Shinnakasu R;Plajer V;Stecher C;Zhao J;Lietzenmayer M;Kroehling L;Takumi A;Kometani K;Inoue T;Kluger Y;Kaech SM;Kurosaki T;Okada T;Flavell RA
通讯作者：
Flavell RA
影响因子：
82.9
作者：
Gattinoni L;Speiser DE;Lichterfeld M;Bonini C
通讯作者：
Bonini C
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：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira