STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer

Wang, Qiwei; Bergholz, Johann S.; Ding, Liya; Lin, Ziying; Kabraji, Sheheryar; Hughes, Melissa E.; He, Xiadi; Xie, Shaozhen; Jiang, Tao; Wang, Weihua; Zoeller, Jason J.; Kim, Hye‐Jung; Roberts, Thomas M.; Konstantinopoulos, Panagiotis A.; Matulonis, Ursula A.; Dillon, Deborah; Winer, Eric P.; Lin, Nancy U.; Zhao, Jean J.

doi:10.1038/s41467-022-30568-1

articleNature CommunicationsMay 31, 2022GOLD OA

STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer

QWQiwei Wang JSJohann S. Bergholz LDLiya Ding ZLZiying Lin SKSheheryar Kabraji

Broad Institute · Harvard University · +5 more institutions

Indexed incrossrefdoaj

Abstract

Abstract PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA -mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor…

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Topics & keywords

Topics

Keywords

Cancer research
Sting
Innate immune system
Immune system
Breast cancer
Immunotherapy
Tumor microenvironment
Biology

UN Sustainable Development Goals

Good health and well-being

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