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

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

  • Nat Commun. 2022 May 31;13(1):3022. doi: 10.1038/s41467-022-30568-1.
Qiwei Wang  # 1 2 3 Johann S Bergholz  # 1 2 3 Liya Ding 1 3 4 Ziying Lin 1 2 5 Sheheryar K Kabraji 1 6 7 Melissa E Hughes 6 Xiadi He 1 2 Shaozhen Xie 1 2 Tao Jiang 1 Weihua Wang 1 Jason J Zoeller 8 Hye-Jung Kim 9 Thomas M Roberts 1 2 Panagiotis A Konstantinopoulos 6 Ursula A Matulonis 6 Deborah A Dillon 10 Eric P Winer 6 Nancy U Lin 6 Jean J Zhao 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 4 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 8 Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10 Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  • 11 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected]
  • 12 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected]
  • 13 Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected]
  • 14 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected]
  • # Contributed equally.
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.

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