第1周
免疫检查点
生物
封锁
癌症研究
人口
免疫系统
免疫学
细胞周期检查点
免疫疗法
癌症
细胞周期
医学
遗传学
受体
细胞周期蛋白依赖激酶1
环境卫生
作者
Ensong Guo,Rourou Xiao,Yifan Wu,Funian Lu,Chen Liu,Bin Yang,Xi Li,Yu Fu,Zizhuo Wang,Li Yuan,Yuhan Huang,Fuxia Li,Xue Wu,Lixin You,Tianyu Qin,Yiling Lu,Xiaoyuan Huang,Ding Ma,Gordon B. Mills,Chaoyang Sun,Gang Chen
摘要
Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell–dependent manner. A WEE1 inhibition–induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.
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