MEK抑制可將CD8+T細胞重編程為抗腫瘤型記憶幹細胞

MEK抑制可將CD8+T細胞重編程為抗腫瘤型記憶幹細胞

作者：

小柯機器人

發布時間：2020/11/25 16:33:57

美國喬治敦大學Samir N. Khleif小組發現，MEK抑制可將CD8⁺T淋巴細胞重編程為具有強大抗腫瘤作用的記憶幹細胞。相關論文於2020年11月23日在線發表在《自然—免疫學》雜誌上。

研究人員發現MEK1/2抑制（MEKi）誘導具有初始表型的再生幹細胞樣記憶（T_SCM），其具有自我更新、增強的多能性和增殖能力。這可以通過延遲細胞分裂並增強線粒體的生物發生和脂肪酸氧化來實現，而又不影響T細胞受體介導的活化。DNA甲基化分析顯示，MEKi誘導的TSCM細胞表現出可塑性和基因座特異性特徵，類似於從健康供體中分離出的真正TSCM，並且與初始和中央記憶T細胞相比具有中間特徵。體外，MEKi處理後CD8⁺T細胞的抗原再攻擊表現出更強的記憶應答。這種策略產生的T細胞具有更高的過繼細胞治療功效。此外，MEKi對荷瘤小鼠的治療也顯示出強大的免疫抗腫瘤作用。

 

總之，研究人員表明，MEKi導致CD8⁺T細胞重編程為TSCM，從而可充當具有高效治療特徵的效應T細胞。

 

據介紹，T_SCM CD8⁺T細胞持續時間更長，並產生更強的效應子功能。

 

附：英文原文

Title: MEK inhibition reprograms CD8 + T lymphocytes into memory stem cells with potent antitumor effects

Author: Vivek Verma, Nazli Jafarzadeh, Shannon Boi, Subhadip Kundu, Zhinuo Jiang, Yiping Fan, Jose Lopez, Rahul Nandre, Peng Zeng, Fatmah Alolaqi, Shamim Ahmad, Pankaj Gaur, Simon T. Barry, Viia E. Valge-Archer, Paul D. Smith, Jacques Banchereau, Mikayel Mkrtichyan, Benjamin Youngblood, Paulo C. Rodriguez, Seema Gupta, Samir N. Khleif

Issue&Volume: 2020-11-23

Abstract: 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.

DOI: 10.1038/s41590-020-00818-9

Source: https://www.nature.com/articles/s41590-020-00818-9