WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway

Ensong Guo, Rourou Xiao, Yifan Wu, Funian Lu, Chen Liu, Bin Yang, Xi Li, Yu Fu, Zizhuo Wang, Yuan Li, Yuhan Huang, Fuxia Li, Xue Wu, Lixin You, Tianyu Qin, Yiling Lu, Xiaoyuan Huang, Ding Ma, Gordon B. Mills, Chaoyang SunGang Chen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbere20210789
JournalJournal of Experimental Medicine
Volume219
Issue number1
DOIs
StatePublished - Nov 26 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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