Journal Article

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

Zoeller, Jason J., Lin, Nancy U., Ding, Liya, Lin, Ziying, He, Xiadi, Kim, Hye-Jung, Wang, Qiwei, Matulonis, Ursula A., Dillon, Deborah A., Winer, Eric P., Kabraji, Sheheryar K., Xie, Shaozhen, Konstantinopoulos, Panagiotis A., Hughes, Melissa E., Jiang, Tao, Roberts, Thomas M., Bergholz, Johann S., Wang, Weihua, Zhao, Jean J.

2022

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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