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

Author

Listed:
  • Irineos Papakyriacou

    (Uppsala University)

  • Ginte Kutkaite

    (Helmholtz Munich
    Ludwig-Maximilians University Munich)

  • Marta Rúbies Bedós

    (Uppsala University)

  • Divya Nagarajan

    (Uppsala University)

  • Liam P. Alford

    (Uppsala University)

  • Michael P. Menden

    (Helmholtz Munich
    University of Melbourne)

  • Yumeng Mao

    (Uppsala University)

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 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.

Suggested Citation

  • Irineos Papakyriacou & Ginte Kutkaite & Marta Rúbies Bedós & Divya Nagarajan & Liam P. Alford & Michael P. Menden & Yumeng Mao, 2024. "Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47987-x
    DOI: 10.1038/s41467-024-47987-x
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