Abstract LB159: Overcoming immunosuppression and therapeutic resistance to PARP inhibition in BRCA1-deficient breast cancer with STING agonists
Authors: Wang Qiwei , Bergholz Johann S. , Ding Liya , Lin Ziying , Xie Shaozhen , Jiang Tao , Kim Hye-Jung , Roberts Thomas M. , Zhao Jean J. 
Published: July 2021

Abstract
PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitor is relatively modest in patients with advanced BRCA-mutant breast cancer, as shown by the final reports on overall survival described by the OlympiAD and EMBRACA clinical trials. We have recently generated in parallel two syngeneic genetically engineered mouse (GEM) models of BRCA1/p53-deficient high-grade serous ovarian cancer (HGSOC) and invasive basal-like breast cancer. Notably, our pre-clinical results of PARPi in these two models are in line with clinical outcomes showing different responses to PARPi between breast and ovarian tumors, which cannot be explained by synthetic lethality alone.
Here, we uncovered a major mechanism by which BRCA1-deficient breast tumors typically progress through treatment with PARPi as monotherapy or in combination with PD-1 blockade, in contrast to the much higher rates of success observed for BRCA1-deficient ovarian cancer. Using our syngeneic GEM model of breast cancer driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) abrogate PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce protumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of cytosolic double-stranded DNA (dsDNA) and synthetic lethality, hence impairing STING-dependent antitumor immunity. STING agonists reprogram M2-like TAMs into an M1-like anti-tumor state in a macrophage STING-dependent fashion. Systemic administration of STING agonists breaches multiple layers of tumor cell-mediated suppression on macrophages and dendritic cells, and synergizes with PARPi. Notably, while STING-deficient/BRCA1-deficient breast tumors fail to respond to the combination of PARPi and STING agonists administered intratumorally, they respond effectively to systemic delivery of STING agonists in combination with PARPi. Our data is thus different from the majority of other studies suggesting that STING agonists act in the tumor cells but is consistent with a rising tide of work pointing to the importance of STING activation in macrophages and DCs. This finding also suggests a novel therapeutic approach for treating a significant fraction of patients with cancers deficient in tumor cell-intrinsic STING.
Together, our study provides an important conceptual shift in understanding the resistance to PARP inhibitors, which has mostly been described in terms of restoration of homologous recombination. Our mechanism-based, novel therapeutic approach to circumvent the refractory nature of BRCA1-deficient breast cancers should prove instrumental in guiding the design of clinical trials evaluating PARPi-based rational combination therapy in the near future.
Citation Format: Qiwei Wang, Johann S. Bergholz, Liya Ding, Ziying Lin, Shaozhen Xie, Tao Jiang, Hye-Jung Kim, Thomas M. Roberts, Jean J. Zhao. Overcoming immunosuppression and therapeutic resistance to PARP inhibition in BRCA1-deficient breast cancer with STING agonists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB159.