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Papakyriacou, I.* ; Kutkaite, G. ; Rúbies Bedós, M.* ; Nagarajan, D.* ; Alford, L.P.* ; Menden, M.P. ; Mao, Y.*

Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer.

Nat. Commun. 15:3581 (2024)

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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 leverage genome-wide CRISPR/Cas9 screens in a Tumor-Immune co-Culture System focusing on triple-negative breast cancer (TNBC). We reveal that NEDD8 loss in cancer cells causes a vulnerability to nivolumab (anti-PD-1). Genetic deletion of NEDD8 only delays cell division initially but cell proliferation is unaffected after recovery. Since the NEDD8 gene is commonly essential, we validate this observation with additional CRISPR screens and uncover enhanced immunogenicity in NEDD8 deficient cells using proteomics. In female immunocompetent mice, PD-1 blockade lacks efficacy against established EO771 breast cancer tumors. In contrast, we observe tumor regression 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 TNBC and presents as a synergistic drug target for PD-1/L1 blockade therapy.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Nedd8-activating Enzyme-inhibitor; Pluripotent Stem-cells; Essential Genes; Double-blind; Neddylation; Chemotherapy; Identification; Pembrolizumab; Resistance; Target

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 15, Issue: 1, Article Number: 3581

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)

Grants
SNIC
Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX)
SciLifeLab Fellows Program
Swedish Cancer Society
Swedish Childhood Cancer Foundation
Swedish Foundation for Strategic Research
Swedish Research Council
European Union
National Genomics Infrastructure