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

Qiwei Wang, Johann S. Bergholz, Liya Ding, Ziying Lin, Sheheryar K. Kabraji, Melissa E. Hughes, Xiadi He, Shaozhen Xie, Tao Jiang, Weihua Wang, Jason J. Zoeller, Hye-Jung Kim, Thomas M. Roberts, Panagiotis A. Konstantinopoulos, Ursula A. Matulonis, Deborah A. Dillon, Eric P. Winer, Nancy U. Lin and Jean J. Zhao ()
Additional contact information
Qiwei Wang: Dana-Farber Cancer Institute
Johann S. Bergholz: Dana-Farber Cancer Institute
Liya Ding: Dana-Farber Cancer Institute
Ziying Lin: Dana-Farber Cancer Institute
Sheheryar K. Kabraji: Dana-Farber Cancer Institute
Melissa E. Hughes: Dana-Farber Cancer Institute
Xiadi He: Dana-Farber Cancer Institute
Shaozhen Xie: Dana-Farber Cancer Institute
Tao Jiang: Dana-Farber Cancer Institute
Weihua Wang: Dana-Farber Cancer Institute
Jason J. Zoeller: Harvard Medical School
Hye-Jung Kim: Dana-Farber Cancer Institute
Thomas M. Roberts: Dana-Farber Cancer Institute
Panagiotis A. Konstantinopoulos: Dana-Farber Cancer Institute
Ursula A. Matulonis: Dana-Farber Cancer Institute
Deborah A. Dillon: Brigham and Women’s Hospital
Eric P. Winer: Dana-Farber Cancer Institute
Nancy U. Lin: Dana-Farber Cancer Institute
Jean J. Zhao: Dana-Farber Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-17

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 immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.

Date: 2022
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DOI: 10.1038/s41467-022-30568-1

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