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

• Published in: Nature communications Vol. 13; no. 1; pp. 3022 - 17
• Main Authors: Wang, Qiwei, Bergholz, Johann S., Ding, Liya, Lin, Ziying, Kabraji, Sheheryar K., 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 A., Winer, Eric P., Lin, Nancy U., Zhao, Jean J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.05.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14; 14/19; 14/63; 38/39; 38/77; 38/91; 42; 42/109; 42/41; 45; 45/61; 45/90; 45/91; 631/67/1059/2325; 631/67/1347; 631/67/580; 64/110; 64/60; 692/4028/67/1059/2325; 96/21; Agonists; Animal models; Animals; BRCA1 protein; BRCA1 Protein - genetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; CD8 antigen; CD8-Positive T-Lymphocytes; Damage; Deoxyribonucleic acid; DNA; DNA damage; Female; Genetic engineering; Humanities and Social Sciences; Humans; Immune system; Immunity; Inhibitors; Interferon; Lethality; Lymphocytes; Lymphocytes T; Macrophages; Mice; multidisciplinary; Mutation; Ovarian cancer; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Science; Science (multidisciplinary); Synthetic Lethal Mutations; Tumor cells; Tumor-Associated Macrophages; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-30568-1

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. PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.