STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer
Abstract
PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors withBRCAmutations. However, the impact of this class of inhibitors in patients with advancedBRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven byBrca1deficiency, 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 31, 2022
- Source ID
- 10.1038/s41467-022-30568-1
Entities
People
- Deborah A. Dillon
- Eric Winer
- Hye‐Jung Kim
- Jason J. Zoeller
- Jean J. Zhao
- Johann S. Bergholz
- Liya Ding
- Melissa E. Hughes
- Nancy U Lin
- Panagiotis A Konstantinopoulos
- Qiwei Wang
- Shaozhen Xie
- Sheheryar Kabraji
- Tao Jiang
- Thomas M. Roberts
- Ursula A. Matulonis
- Weihua Wang
- Xiadi He
- Ziying Lin
Organizations
- National Institutes of Health
- United States Department of Defense
- United States Department of Health and Human Services