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 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.

Drug-induced adaptation along a resistance continuum in cancer cells

“…Increased expression of interferon genes (IFI27, ISG15, MX1, JAK1) corroborated an early and acute response to PARPi as observed in vitro (Fig. 5g, Supplementary Table 6) and exposes a therapeutic vulnerability with synergistic effects in combination immunotherapy (52,53). In addition, we detected markers that show dose-dependent expression, including genes involved with oxidative stress response (DCXR, QSOX1, SQSTM1) and its master regulator NFE2L2 (Supplementary Fig.…”

PTEN and BRCA1 tumor suppressor loss associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in a murine model of ovarian cancer

“…In mice treated with STING agonist, we observed a shift from M2 to M1 macrophages. This finding is in concordance with a similar recent study in both colorectal cancer and breast cancer models where repolarization of M2 macrophages to a M1 phenotype was observed upon exogenous STING pathway activation 30,39 . This suggests that STING pathway activation in Pten deficient HGSC displays the benefits associated with decreased M2s, such as decreased angiogenesis, secretion of immunosuppressive cytokines such as IL-10 and TGF-β, while providing rationale for the combined use of STING agonists and immune checkpoint blockade therapy, particularly PD-L1 antagonism.…”

A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses

“…This phenomenon could be explained by the intrinsically high mannose receptor (CD206) expression levels in M2 macrophages and the resultant cGAS-STING stimulation (Fig. 7b, c ) 55 . Considering the immunostimulatory functions of M1 macrophages in various immunotherapeutic designs, the nanoagonist-mediated M2-to-M1 macrophage repolarization may alleviate the immunosuppression in the TME and enhance the eventual T cell-mediated antitumor efficacy.…”