Alireza Khodadadi-Jamayran

PARP Inhibitors Differentially Regulate Immune Responses in Distinct Genetic Backgrounds of High-Grade Serous Tubo-Ovarian Carcinoma

Abstract Immune checkpoint inhibitors (ICI) have revolutionized treatment for several tumor indications without demonstrated benefit for patients with ovarian cancer. To improve the therapeutic ratio of ICIs in patients with ovarian cancer, several different clinical trials are testing combinations with poly(ADP-ribose) polymerase (PARP) inhibitors. Comparing the immunomodulatory effects of clinically advanced PARP inhibitors (PARPi) may help to identify the best partner to combine with ICIs. We examined the treatment effect of talazoparib (a PARP trapper) and veliparib (a solely PARP enzymatic inhibitor) in homologous recombination deficient (HRD) and homologous recombination proficient high-grade serous tubo-ovarian carcinoma (HGSC) cell lines on immune-related gene expression. We discovered and validated that CXCL8, IL-6, and TNF gene expression were upregulated after talazoparib treatment in both OVCAR3 (HRD) and CAOV3 homologous recombination proficient HGSC cell lines. In contrast, veliparib treatment slightly elevated similar genes exclusively in an HRD HGSC cell line model. We expanded these studies to include olaparib, a PARP trapper less potent than talazoparib, and found effects specific to COV361 (BRCA1 mutant) and OVCAR8 (BRCA1 methylated) HGSC cells but not all HRD HGSC cell lines. Our studies also identified differences among PARP trappers versus veliparib on augmenting CXCL10 expression. Finally, we show that talazoparib modulates the CXCL10 response in cGAS-defective cell lines, independent of the cGAS-STING pathway. These mechanistic studies advance our understanding of how different PARPis affect the immune system in various genetic backgrounds. Significance: This work highlights how different PARPis, especially talazoparib, modulate immune-related gene expression in ovarian cancer cells, independent of the cGAS-STING pathway. These findings may improve our understanding of how different PARPis affect the immune system in various genetic backgrounds.