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研究揭示CDK7能够增强抗肿瘤免疫
作者:小柯机器人 发布时间:2019/12/27 15:06:37

美国纽约大学朗格尼医学中心Kwok-Kin Wong研究组发现,细胞周期蛋白依赖性激酶7(CDK7)的抑制增强了基因组的不稳定性,从而在小细胞肺癌(SCLC)中触发抗肿瘤免疫。该研究于2019年12月26日发表于国际学术期刊《癌细胞》。

使用选择性的CDK7抑制剂YKL-5-124,他们证明抑制CDK7主要破坏细胞周期进程,并诱导DNA复制压力和SCLC中的基因组不稳定,同时触发免疫反应信号传导。这些肿瘤内在事件激发了由T细胞引发的强大的免疫监视程序,通过增强免疫检验点的封闭进一步增强了免疫监视程序。 YKL-5-124与抗PD-1的结合在SCLC的多种高度侵袭性小鼠模型中占据着显著的生存优势,为由CDK7抑制剂和免疫疗法组成的新联合疗法提供了理论依据。

研究人员表示, CDK7是细胞周期和基因转录的中央调节器。但是,对其基因组不稳定性和癌症免疫力的影响知之甚少。

附:英文原文

Title: CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer

Author: Hua Zhang, Camilla L. Christensen, Ruben Dries, Matthew G. Oser, Jiehui Deng, Brian Diskin, Fei Li, Yuanwang Pan, Xuzhu Zhang, Yandong Yin, Eleni Papadopoulos, Val Pyon, Cassandra Thakurdin, Nicholas Kwiatkowski, Kandarp Jani, Alexandra R. Rabin, Dayanne M. Castro, Ting Chen, Heather Silver, Qingyuan Huang, Mirna Bulatovic, Catríona M. Dowling, Belen Sundberg, Alan Leggett, Michela Ranieri, Han Han, Shuai Li, Annan Yang, Kristen E. Labbe, Christina Almonte, Vladislav O. Sviderskiy, Max Quinn, Jack Donaghue, Eric S. Wang, Tinghu Zhang, Zhixiang He, Vamsidhar Velcheti, Peter S. Hammerman, Gordon J. Freeman, Richard Bonneau, William G. Kaelin, Kate D. Sutherland, Ariena Kersbergen, Andrew J. Aguirre, Guo-Cheng Yuan, Eli Rothenberg, George Miller, Nathanael S. Gray, Kwok-Kin Wong

Issue&Volume: December 26, 2019

Abstract: Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.

DOI: 10.1016/j.ccell.2019.11.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30523-9

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx