@article{aa193b7e7df44201866687b70866b31b,
title = "WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway",
abstract = "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 upregulates 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. AWEE1 inhibition-induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy withWEE1 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.",
author = "Ensong Guo and Rourou Xiao and Yifan Wu and Funian Lu and Chen Liu and Bin Yang and Xi Li and Yu Fu and Zizhuo Wang and Yuan Li and Yuhan Huang and Fuxia Li and Xue Wu and Lixin You and Tianyu Qin and Yiling Lu and Xiaoyuan Huang and Ding Ma and Mills, {Gordon B.} and Chaoyang Sun and Gang Chen",
note = "Funding Information: The current studies were supported by the Nature and Science Foundation of China (81874106 to G. Chen, 81974408 to C. Sun, 82002762 to E. Guo, and 82060472 to F. Li). G.B. Mills has support from the National Institutes of Health (P50CA217685 and U01 CA217842), Susan G. Komen Breast Cancer Foundation (SAC110052), the Breast Cancer Research Foundation, and a kind gift from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Funding Information: Disclosures: G.B. Mills reported grants from Amphista, As-traZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symph-ogen, Tarveda, Turbine, Zentalis Pharmaceuticals, Catena Pharmaceuticals, HRD assay to Myriad Genetics, DSP to Nanostring, Adelson Medical Research Foundation, Breast Cancer Research Foundation, Komen Research Foundation, Ovarian Cancer Research Foundation, Prospect Creek Foundation, Nanostring Center of Excellence, Ionis (Provision of tool compounds), and Genentech during the conduct of the study; and personal fees, non-financial support, and “other” from Amphista, AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, Zentalis Pharmaceuticals, Catena Pharmaceuticals, HRD assay to Myriad Genetics, DSP to Nanostring, Adelson Medical Research Foundation, Breast Cancer Research Foundation, Ko-men Research Foundation, Ovarian Cancer Research Foundation, Prospect Creek Foundation, Nanostring Center of Excellence, Ionis (Provision of tool compounds), and Genentech outside the submitted work. No other disclosures were reported. Publisher Copyright: {\textcopyright} 2021 Guo et al.",
year = "2021",
month = nov,
day = "26",
doi = "10.1084/jem.20210789",
language = "English (US)",
volume = "219",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "1",
}