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

Irineos Papakyriacou1, Ginte Kutkaite2,3, Marta Rúbies Bedós1

  • 1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Nature Communications
|April 27, 2024
PubMed

Insights

Targeting NEDD8 in triple-negative breast cancer (TNBC) enhances immune checkpoint blockade therapy. Loss of NEDD8 makes TNBC cells vulnerable to PD-1 blockade, improving immunotherapy efficacy.

Area of Science:

  • Immunology
  • Oncology
  • Genetics

Background:

  • Immune checkpoint blockade therapy shows limited efficacy in a subset of cancer patients.
  • Triple-negative breast cancer (TNBC) remains a challenging malignancy with limited treatment options.

Purpose of the Study:

  • To identify novel therapeutic targets for enhancing immune checkpoint blockade in TNBC.
  • To investigate the role of NEDD8 in TNBC response to PD-1 blockade.

Main Methods:

  • Genome-wide CRISPR/Cas9 screens in a co-culture system of tumor and immune cells.
  • Proteomic analysis to assess immunogenicity of NEDD8-deficient cells.
  • In vivo studies using immunocompetent mice bearing EO771 breast cancer tumors.

Main Results:

  • NEDD8 loss in cancer cells sensitizes them to nivolumab (anti-PD-1) therapy.
  • NEDD8-deficient cells exhibit enhanced immunogenicity.
  • PD-1 blockade effectively regresses established Nedd8-deficient EO771 tumors in mice, mediated by CD8+ T cells.

Conclusions:

  • NEDD8 is conditionally essential in TNBC and represents a potential synergistic target for PD-1/L1 blockade.
  • Targeting NEDD8 could improve clinical benefits of immunotherapy for TNBC patients.

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