MEK抑制通过下调c-Fos和JunB阻止CAR-T细胞耗竭和分化-动脉网

MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB

Nature 等信源发布 2024-10-22 22:16

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AbstractClinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy.

。MEK1/2抑制剂（MEKIs）由于其抑制异常MAPK信号传导的能力而广泛用于癌症治疗，当与免疫疗法结合使用时，已显示出潜在的协同作用。

However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors.

然而，MEKIs对CAR-T细胞的影响和机制仍然不确定和有争议。为了解决这个问题，我们进行了全面的调查，以确定MEKIs是否增强或削弱CAR-T细胞的功效。我们的研究结果表明，MEKIs减弱了由强直信号传导和抗原刺激诱导的CAR-T细胞耗竭和终末分化，从而提高了CAR-T细胞对血液学和实体瘤的疗效。

Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB.

值得注意的是，这些作用与CAR中使用的特定scFv和共刺激结构域无关。从机理上讲，对大量和单细胞转录谱的分析表明，MEK抑制的作用与减少合成代谢和下调c-Fos和JunB有关。

Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation.

此外，CAR-T细胞中c-Fos或JunB的过表达抵消了MEK抑制的作用。此外，我们的切割和标签测定显示MEK抑制下调了与衰竭，分化，无能，糖酵解和细胞凋亡相关的JunB驱动的基因谱。总之，我们的研究揭示了MAPK-c-Fos-JunB轴在驱动CAR-T细胞衰竭和终末分化中的关键作用。

These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy..

这些机制的见解大大拓宽了MEKIs的潜在应用范围，以提高CAR-T治疗的有效性。。

IntroductionOncogenic mutation targeted therapy has shown responses in tumors harboring mutated oncogenes such as mutant BRAF.1 However, targeted therapy is generally not curative because secondary mutations and transcriptional alterations often confer resistance to the primary therapy.2 Chimeric antigen receptors (CARs) are synthetic receptors targeting tumor antigens.3 CAR-T therapy has shown potent efficacy in relapsed or refractory B-cell malignancies,3 even those resistant to targeted therapy.4 Nevertheless, the limited persistence of CAR-T cells due to T cell exhaustion and terminal differentiation has restricted post-CAR-T survival of patients in both B-cell malignancies and solid tumors.3,5Chronic CAR signaling is one of the intrinsic causes of CAR-T cell exhaustion and terminal differentiation.6,7 According to whether the initiation of CAR signaling needs antigen binding, CAR signaling can be categorized into low-level basal tonic signaling (independent of antigen stimulation),6,8,9 and antigen-dependent high-level signaling.7,9 Tonic signaling results from the self-aggregation of CAR molecules independent of antigen stimulation.6,10 Thus, its downstream signaling cascade molecules are the same as those activated by CAR clustering due to antigen binding.

，6,8,9和抗原依赖性高水平信号传导[7,9]。强直信号传导是由CAR分子的自聚集产生的，而不依赖于抗原刺激[6,10]。因此，其下游信号级联分子与由于抗原结合而被CAR聚类激活的分子相同。

The primary differences between tonic signaling and antigen-dependent signaling are the trigger (with or without antigen stimulation) and the signaling intensity (low versus high). Considering that many targets of targeted agents are also crucial signaling molecules in CAR-T cells, combining CAR-T and targeted therapy may be a promising way to prolong the persistence of CAR-T cells and overcome the shortcomings of respective monotherapy.

紧张信号和抗原依赖性信号之间的主要区别是触发（有或没有抗原刺激）和信号强度（低与高）。。

Unfortunately, the inhibition of these signaling molecules might also impa.

不幸的是，这些信号分子的抑制也可能会影响。

Data availability

数据可用性

Raw genomics data from human samples have been deposited at China National Gene Bank, and accession number is CNP0002478. Data will be released on Nov.5th, 2024. Any additional information required to reanalyze the data reported in this paper is available from the corresponding author upon request.

来自人类样本的原始基因组学数据已保存在中国国家基因库，登录号为CNP0002478。数据将于2024年11月5日发布。重新分析本文报告的数据所需的任何其他信息均可应要求从通讯作者处获得。

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Download referencesAcknowledgementsThis work was supported by the National Key Research and Development Program of China (2022YFA1103500 to P.Q.), the National Key Nature Science Foundation of China (82130003 to H.H.), the Key Project of Science and Technology Department of Zhejiang Province (2019C03016 and 2020C03G2013586 to H.H., Z24H080001 to P.Q.), the National Natural Science Foundation of China (82200248 and 82000194 to H.H., 82222003 and 82161138028 to P.Q.), the Key R&D Program of Zhejiang (2024SSYS0023 to H.H., 2024SSYS0024 to P.Q., 2024SSYS0025 to Y.H.), and the Fundamental Research Funds for the Central Universities (226-2024-00007 to P.Q.).

下载参考文献致谢这项工作得到了国家重点研究发展计划（2022YFA1103500至P.Q.），国家重点自然科学基金（82130003至H.H.），浙江省科学技术厅重点项目（2019C03016和2020C03G2013586至H.H.，Z24H080001至P.Q.），国家自然科学基金（82200248和82000194至H.H.，82222003和82161138028至P.Q。），浙江省重点研发计划（2024SSYS0023至H.H.，2024SSYS0023至H.24至P.Q.，2024SSYS0025至Y.H.），以及中央大学基础研究基金（226-2024-00007至P.Q.）。

The author P.Q. gratefully acknowledges the support of K.C. Wong Education Fundation. We thank the staff members Lingli Yang, Feiyan Zheng, Qi Lou, Qiaojuan Shi, Ting Xu, and Liangliang Zhu of the Animal Facility at Zhejiang Academy of Medical Sciences for providing support in mouse housing and care, the staff members Yingying Huang, Jiajia Wang, Chun Guo and Xinghui Song of Core Facilities, Zhejiang University School of Medicine for technical supports, and the donors for donation of blood.Author informationAuthor notesThese authors contributed equally: Xiujian Wang, Xiao Tao, Pengjie Chen, Penglei Jiang, Wenxiao LiAuthors and AffiliationsBone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaXiujian Wang, Xiao Tao, Pengjie Chen, Wenxiao Li, Hefeng Chang, Cong Wei, Xinyi Lai, Yihan Pan, Lijuan Ding, Zuyu Liang, Jiazhen Cui, Mi Shao, Xinyi Teng, Tianning Gu, Jieping Wei, Delin Kong, Xiaohui Si, Yingli Han, Huarui Fu, Yu Lin, Jian Yu, Xia Li, Dongrui Wang, Yongxian Hu & He HuangLiangzhu Laboratory, Zhejiang University Medical Center, .

作者P.Q.非常感谢K.C.Wong教育基金会的支持。我们感谢浙江省医学科学院动物设施的工作人员杨凌丽，郑飞燕，齐楼，石巧娟，徐婷和朱良良在小鼠饲养和护理方面提供的支持，浙江大学医学院核心设施的工作人员黄英英，王佳佳，郭春春和宋兴辉的技术支持，以及献血者的献血。作者信息作者注意到，这些作者做出了同样的贡献：王秀健，肖涛，陈鹏杰，蒋鹏磊，温晓作者和附属机构浙江大学医学院第一附属医院骨髓移植中心，杭州，310003，中国王秀健，王晓涛，陈鹏杰，李文孝，常鹤峰，丛伟，赖信义，潘一汉，丁丽娟，梁祖玉，崔佳珍，米绍，滕信义，顾天宁，魏杰平，孔德林，斯晓辉，韩英利，傅华瑞，于林，于宇，夏丽，王东瑞，胡永贤和何浙江大学医学中心黄良珠实验室。

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PubMed Google ScholarContributionsH.H. and P.Q. designed the study, analyzed and interpreted the data, and revised the manuscript. X.W. designed the study, performed the experiments, analyzed and interpreted the data, and wrote the manuscript. X.T., P.C., W.L., H.C., X.L., and Y.P.

PubMed谷歌学术贡献。H、和P.Q.设计了这项研究，分析和解释了数据，并修改了手稿。十、 W.设计了这项研究，进行了实验，分析和解释了数据，并撰写了手稿。十、 T.，P.C.，W.L.，H.C.，X.L。和Y.P。

performed the experiments. H.Z., Y.X.H., J.Y., and D.W. contribute to the partial study design. P.J. and X.W. analyzed and interpreted the bulk and single-cell transcriptome and Cut & Tag data. X.W., XT., P.J., and C.W. drew the figure. C.W. performed the western blot and partial ex-vivo experiments.

进行了实验。H、 Z.，Y.X.H.，J.Y。和D.W.为部分研究设计做出了贡献。P、 J.和X.W.分析并解释了大量和单细胞转录组以及切割和标记数据。十、西，下。，P、 J.和C.W.绘制了该图。C.W.进行了蛋白质印迹和部分离体实验。

H.Z., Z.L., L. D., J.C., M.S., X. T., T. G., D.K., J.W.,H. F., X.S., H.C., Y.P., X.L., Y.L.H., and Y.L. contribute to CAR-T cell culture. All authors read and approved the final manuscript.Corresponding authorsCorrespondence to.

H、 Z.，Z.L.，L.D.，J.C.，M.S.，X.T.，T.G.，D.K.，J.W.，H.F.，X.S.，H.C.，Y.P.，X.L.，Y.L.H。和Y.L.有助于CAR-T细胞培养。所有作者都阅读并批准了最终稿件。通讯作者通讯。

Pengxu Qian or He Huang.Ethics declarations

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Reprints and permissionsAbout this articleCite this articleWang, X., Tao, X., Chen, P. et al. MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB.

转载和许可本文引用本文Wang，X.，Tao，X.，Chen，P。等人。MEK抑制通过下调c-Fos和JunB来防止CAR-T细胞耗竭和分化。

Sig Transduct Target Ther 9, 293 (2024). https://doi.org/10.1038/s41392-024-01986-yDownload citationReceived: 27 November 2023Revised: 26 August 2024Accepted: 18 September 2024Published: 22 October 2024DOI: https://doi.org/10.1038/s41392-024-01986-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sig Transduct Target Ther 9293（2024）。https://doi.org/10.1038/s41392-024-01986-yDownload引文接收日期：2023年11月27日修订日期：2024年8月26日接受日期：2024年9月18日发布日期：2024年10月22日OI：https://doi.org/10.1038/s41392-024-01986-yShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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