NEDD8 loss causes cancer vulnerability to immune checkpoint blockade in triple-negative breast cancer

NEDD8 loss causes cancer vulnerability to immune checkpoint blockade in triple-negative breast cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article NEDD8 loss causes cancer vulnerability to immune checkpoint blockade in triple-negative breast cancer Yumeng Mao, Irineos Papakyriacou, Ginte Kutkaite, Marta Rubies Bedos, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2687913/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Apr, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Immune checkpoint blockade therapy aims to activate the immune system to eliminate cancer cells. However, clinical benefits are only recorded in a subset of patients. Here, we leveraged genome-wide CRISPR/Cas9 screens in a Tumor-Immune co-Culture System focusing on triple-negative breast cancer. We revealed that NEDD8 loss caused a vulnerability to nivolumab. Genetic deletion of NEDD8 only delayed cell division initially but cell proliferation was unaffected after recovery. Since the NEDD8 gene is commonly essential, we validated this paradigm shift with additional CRISPR screens and uncovered significantly enhanced immunogenicity in NEDD8 deficient cells using proteomics. In immunocompetent mice, PD-1 blockade lacked efficacy against established EO771 breast cancer tumors. In contrast, we observed curative effects mediated by CD8+ T cells against NEDD8 deficient EO771 tumors after PD-1 blockade. In essence, we provide evidence that NEDD8 is conditionally essential in triple-negative breast cancer and presents a synergistic drug target for PD-1/L1 blockade therapy. Biological sciences/Cancer/Tumour immunology Biological sciences/Cell biology/Post-translational modifications/Neddylation Full Text Additional Declarations Yes there is potential Competing Interest. Y.M. and M.P.M. were former employees of AstraZeneca and hold company shares. Y.M. received funding from Bayer Pharmaceuticals and Novo Nordisk Foundation for unrelated projects. M.P.M. receives funding from Roche and GSK for other projects. Other authors declare no conflict of interest. Supplementary Files DataS1gRNAcounts.xlsx Data S1 gRNA counts from CRISPR screens DataS2NEDD8KOproteomics.xlsx Data S2 Proteomics analysis of control or NEDD8 KO cells DataS3normaliseddatananostring.xlsx Data S3 Normalized RNA counts for nanostring analysis 20240226reagenttableR2.pdf Table S1-S4 nrreportingsummaryPapakyriacouetalprint.pdf Reporting summary Cite Share Download PDF Status: Published Journal Publication published 27 Apr, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2687913","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":281079903,"identity":"1ff1664d-d580-46db-a409-a5b662368191","order_by":0,"name":"Yumeng 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