| Accession | PRJCA003880 | ||||||||||||||||
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| Title | WEE1 Inhibition Induces Anti-tumor Immunity and Responsiveness to Checkpoint Blockade by Activating ERV and the dsRNA Pathway | ||||||||||||||||
| Relevance | Medical | ||||||||||||||||
| Data types |
Epigenomics
Transcriptome or Gene expression |
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| Organisms |
Mus musculus
Homo sapiens |
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| Description | Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or interdict emergence of resistance. Here we demonstrate that targeting WEE1 upregulates immune signaling through dsRNA viral defense pathway with subsequent responsiveness to immune checkpoint blockade (ICB). WEE1 inhibition increases expression of endogenous retroviral elements (ERVs) by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs triggers double-stranded RNA (dsRNA) stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combined WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell-dependent manner. AZD1775 induced a viral defense signature that correlates with response to WEE1 inhibition combined with ICB, providing a potentially informative biomarker for patient selection. Thus, WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for combination of WEE1 inhibitors and ICB in clinical trials. | ||||||||||||||||
| Sample scope | Multispecies | ||||||||||||||||
| Release date | 2021-09-18 | ||||||||||||||||
| Grants |
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| Submitter | Chaoyang Sun (suncydoctor@gmail.com) | ||||||||||||||||
| Organization | Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology | ||||||||||||||||
| Submission date | 2020-11-17 |