Pharmaceutical STING activation reduces tumor recurrence of triple negative breast cancer and increases survival

Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer for which there is a lack of efficacious targeted therapies. Consequently, TNBC patients are more likely to develop recurrent metastatic disease and experience higher mortality rates than patients with other breast cancer subtypes. The development of recurrent metastatic disease is influenced by cytokines, chemokines, and growth factors in the tumor microenvironment (TME). Oncostatin M (OSM), an IL-6 family member cytokine, induces a stem-like/mesenchymal phenotype in cancer cells – defined by enhanced tumor-initiating capacity, therapy resistance, and increased cell migration/invasion – and primarily supports a pro-tumorigenic tumor immune microenvironment (TIME). In contrast, interferon-β (IFN-β) represses the stem-like/mesenchymal phenotype in cancer cells and primarily supports an anti-tumorigenic TIME. Importantly, OSM signaling represses IFN-β production and its downstream signaling via suppression of innate immune sensors, however one such sensor – stimulator of interferon genes (STING) – is inexplicably increased by OSM. Given that STING agonists are currently in clinical trials for several types of cancer, we sought here to assess the potential therapeutic efficacy of pharmaceutical STING activation on TNBC. The impact of STING activation on IFN-β production and cell migratory capacity in TNBC cells was assessed in vitro using qPCR, western blotting, and a chemotaxis assay. A syngeneic mouse model of metastatic TNBC was used to assess the impact of pharmaceutical STING activation on primary tumor recurrence and metastasis. Flow cytometry and cytokine/chemokine arrays were used to identify how STING agonists impact the TIME. Pharmaceutical STING activation reactivates basal IFN-β production and downstream autocrine signaling in stem-like/mesenchymal TNBC cells and decreases their migratory capacity. Furthermore, pharmaceutical STING activation decreases primary tumor recurrence and extends survival in vivo. Analysis of the TIME at the primary tumor reveals that STING agonism increases NK cell frequency and myeloid-derived suppressor cell (MDSC) frequency while STING agonism increases CD8 + T cell frequency in pulmonary metastases. Pharmaceutical STING activation increases survival in a murine model of metastatic TNBC by reducing primary tumor recurrence but does not prevent metastatic outgrowth likely due to recruiting both pro- and anti-tumorigenic immune cells to the TIME.