PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors

Anna D. Staniszewska & Viia Valge-Archer et al. · 2022-06-18

PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased DNA damage and subsequent immune activation can prime an anti-tumor immune response, we studied the impact of olaparib ± immune checkpoint blockade (ICB) on anti-tumor activity and the immune microenvironment. Concurrent combination of olaparib, at clinically relevant exposures, with ICB gave durable and deeper anti-tumor activity in the Brca1m BR5 model vs. monotherapies. Olaparib and combination treatment modulated the immune microenvironment, including increases in CD8+ T cells and NK cells, and upregulation of immune pathways, including type I IFN and STING signaling. Olaparib also induced a dose-dependent upregulation of immune pathways, including JAK/STAT, STING and type I IFN, in the tumor cell compartment of a BRCA1m (HBCx-10) but not a BRCA WT (HBCx-9) breast PDX model.
Authors
Anna D. Staniszewska, Joshua Armenia, Matthew King, Chrysiis Michaloglou, Avinash Reddy, Maneesh Singh, Maryann San Martin, Laura Prickett, Zena Wilson, Theresa Proia, Deanna Russell, Morgan Thomas, Oona Delpuech, Mark J. O’Connor, Elisabetta Leo, Helen Angell, Viia Valge-Archer