STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis

Abstract

Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by anti-tumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor Stat3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathological analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, non-metastatic Stat3-deficient mammary tumors escaped immune surveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3 inhibitory strategies that may reactivate the immunosurveillance program.

The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression

“…A recent study provided the first experimental evidence that STAT3 is essential for the establishment of immunosuppression during the earliest stages of breast cancer progression34. This is consistent with our observations that mammary epithelial STAT3 loss profoundly impairs breast cancer development in immunocompetent, but not immunodeficient, mice.…”

The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment

“…In addition to modulating macrophage infiltration, our recent studies have indicated that epithelial activation Stat3 plays a critical role in maintaining an immune-suppressive tumor microenvironment. For example, mammary epithelial deletion of Stat3 in PyV mT model results in rapid immune-mediated clearance of emerging PyV mT tumors 22 . Collectively, these observations argue that the potent transforming properties of ErbB2Δ16 variant is due to its impact on the tumor immune microenvironment.…”

The roles of microglia macrophages in tumor progression of brain cancer and metastatic disease

“…These M2 cells have a pro-tumor immune response by producing immunosuppressive factors (e.g., IL-10 and TGF-β) and exhibit a high level of intracellular STAT3 (16). STAT3 activation has also been associated with promoting immunosuppression (45). Activated STAT3 decreases the expression of surface molecules in microglia that are necessary for antigen presentation, such as MHC-II, CD80, and CD86, and also increases the expression of various M2-specific immunomodulatory mediators including IL-10, vascular endothelial growth factor (VEGF), and various matrix metalloproteinases (MMPs) (46, 47), promoting growth and invasion of the tumor.…”