2. Academic Validation
  3. WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway

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

  • J Exp Med. 2022 Jan 3;219(1):e20210789. doi: 10.1084/jem.20210789.
Ensong Guo  # 1 2 3,  Rourou Xiao  # 1 2 3,  Yifan Wu  # 1 2 3 4,  Funian Lu  # 1 2 3,  Chen Liu 1 2 3,  Bin Yang 1 2 3,  Xi Li 1 2 3,  Yu Fu 1 2 3,  Zizhuo Wang 1 2 3,  Yuan Li 1 2 3,  Yuhan Huang 1 2 3,  Fuxia Li 5,  Xue Wu 1 2 3,  Lixin You 1 2 3,  Tianyu Qin 1 2 3,  Yiling Lu 6,  Xiaoyuan Huang 1 2 3,  Ding Ma 1 2 3,  Gordon B Mills 7,  Chaoyang Sun 1 2 3,  Gang Chen 1 2 3
Affiliations

Affiliations

  • 1 National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Gynecology and Obstetrics, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Gynecology Oncology, Guangzhou Women and Children's Hospital, Guangzhou, China.
  • 6 Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
  • 7 Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health and Sciences University, Portland, OR.
  • # Contributed equally.
PMID: 34825915 DOI: 10.1084/jem.20210789
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 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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