Reversal of T cell exhaustion enables cancer vaccine efficacy in BRCA1-deficient ovarian cancer.

BRCA mutations in ovarian cancer (OC) are associated with increased tumor-infiltrating lymphocytes and inflammatory features, yet immunotherapy for OC has shown limited efficacy. Using the ID8 mouse model, we discovered that Brca1 deficiency-but not Brca2-impairs the effectiveness of a dendritic cell-based cancer vaccine (OCDC). OCDC vaccine reduced tumor growth and improved survival in mice bearing Trp53 -/- and Trp53 -/- Brca2 -/- tumors but was ineffective against Trp53 -/- Brca1 -/- tumors. Transcriptomic analysis revealed metabolic and immunologic reprogramming in OCDC-responsive tumors, whereas Brca1 -/- tumors remained refractory. Vaccine inefficacy was associated with a pre-existing inflamed microenvironment, enriched in activated yet exhausted T cells, limiting further immune stimulation by vaccination. Combining OCDC with anti-VEGF and PARP inhibitors partially restored vaccine efficacy in Brca1 -/- tumors, while addition of anti-PD-1 further enhanced T cell function and promoted long-term survival. These findings highlight BRCA1's role in cancer vaccine sensitivity and support rational combination immunotherapies for BRCA1-mutated OC.