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

Abstract

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. In vitro , olaparib induced BRCAm tumor cell–specific dendritic cell transactivation. Relevance to human disease was assessed using patient samples from the MEDIOLA (NCT02734004) trial, which showed increased type I IFN, STING, and JAK/STAT pathway expression following olaparib treatment, in line with preclinical findings. These data together provide evidence for a mechanism and schedule underpinning potential benefit of ICB combination with olaparib.

Auranofin Synergizes with the PARP Inhibitor Olaparib to Induce ROS-Mediated Cell Death in Mutant p53 Cancers

“…Olaparib treatment was associated with an activated effector T-cell response and reduction of immune-checkpoint receptor expression in in vivo models of BRCA1-deficient ovarian cancer [ 76 ]. In addition, olaparib treatment drove immune cell infiltration and activation, and the expression of immune STING/Type I IFN pathways in a BRCA mouse model [ 77 ]. Next to immune related pathway, we also checked the effect of AF, olaparib and the combination on cell cycle, apoptosis and DNA repair pathways.…”

Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints

“…Of note, olaparib-induced increase in terms of CD8+ T cell recruiting in the TME has been shown to be mediated by the tumor cGAS/STING pathway, an effect more obvious in HR-defective than in HR-proficient TNBC cells [ 87 ]. The preferential stimulation of STING/TBK1/IRF3 pathway in BRCA1-defective tumors has been confirmed by further in vivo studies [ 99 ], speaking in favor of a prediction for greater intra-tumor T cell penetration in BRCA1-defective cancers and of a more modest effect of combined therapy in tumors with a proficient HR system [ 86 ].…”

Facing inevitable PARPis resistance: Mechanisms and therapeutic strategies for breast cancer treatment

“…Increased cellular DNA damage induced by PARPis treatment of BRCA‐mutant tumours and activation of the type I IFN pathway via cGAS‐STING signalling have pleiotropic effects on the immune response, including promotion of dendritic cell (DC) maturation, release of interferons, and initiation of antitumour T‐cell immune responses 82 …”

“…81 Increased cellular DNA damage induced by PARPis treatment of BRCA-mutant tumours and activation of the type I IFN pathway via cGAS-STING signalling have pleiotropic effects on the immune response, including promotion of dendritic cell (DC) maturation, release of interferons, and initiation of antitumour T-cell immune responses. 82 Qiwei Wang et al found that PARPi had limited effects on BRCA1-mutated BC because of the tumourassociated macrophages (TAMs), which hampered the PARPi-induced breast cell DNA damage. But the addition of STING agonist could shift the TAMs phenotype to the anti-tumorigenic M1-like state to be benefit of restoring the PARPi's SL response in BRCA1-deficient BC of mouse models.…”