2. Academic Validation
  3. 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. jean_zhao@dfci.harvard.edu.
  • 12 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. jean_zhao@dfci.harvard.edu.
  • 13 Broad Institute of Harvard and MIT, Cambridge, MA, USA. jean_zhao@dfci.harvard.edu.
  • 14 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. jean_zhao@dfci.harvard.edu.
  • # Contributed equally.
PMID: 35641483 DOI: 10.1038/s41467-022-30568-1
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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