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

Methods

We used the syngeneic orthotopic ID8 mouse ovarian tumor models deficient for Trp53, Trp53 and Brca1, or Trp53 and Brca2. Tumor-implanted mice were vaccinated with a dendritic cell-based whole tumor lysate vaccine (termed OCDC) alone or in combination with anti-VEGF therapy, PARP inhibitor, and/or anti-PD-1 immune checkpoint inhibitor. Tumor burden, mice survival and monitoring of T cell responses were evaluated by bioluminescence imaging, flow cytometry and interferon gamma (IFNg)-ELISpot assay.

Transcriptomic profiling of tumor cell and immune cell-compartments was performed using NanoString GeoMx digital spatial profiling. Results: Brca1 deficiency—but not Brca2— impairs effectiveness of OCDC vaccine. OCDC vaccine reduced tumor growth rates and improved survival of mice implanted with Trp53-/- and Trp53-/-Brca2-/-ID8 tumors, but was ineffective in mice implanted Trp53-/-Brca1-/- tumor model.

Transcriptomic analysis revealed that tumors responsive to OCDC (Brca wild-type or Brca2-/-) underwent metabolic and immunologic reprogramming post-vaccination, unlike Brca1-/- tumors. Inefficacy of the cancer vaccine was driven by a tumor microenvironment that was already inflamed, characterized by a high level of activated yet exhausted T cells, which hinder additional immune activation by vaccination. Combining OCDC with anti-VEGF and PARP inhibitors partially overcame vaccine resistance in Brca1-/- tumors, while adding anti-PD-1 further improved vaccine effectiveness by boosting T cell activity and promoting long-term survival.

Conclusion: These findings highlight BRCA1’s role in cancer vaccine sensitivity and support using rational combinations to overcome vaccine inefficacy in BRCA1-mutated OC.