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

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.