The Epithelial-to-Mesenchymal Transition (EMT) is a cell-biological process that drives the metastatic dissemination of tumor cells and results in invasiveness, acquisition of tumor-initiating properties and elevated resistance to treatment regimes. Using novel in vivo models of epithelial and mesenchymal breast carcinomas, I have demonstrated that epithelial tumors are heavily infiltrated with biologically active CD8+ cytotoxic T-cells, and contain low levels of immunosuppressive Tregs. In contrast, the more mesenchymal tumors exclude exhausted, CD8+ cytotoxic T-cells and recruit immunosuppressive Tregs and pro-tumor, M2-like macrophages instead. Most importantly, epithelial tumors are largely sensitive to anti-CTLA4 immunotherapy, whereas the mesenchymal tumors are resistant. These findings suggest that mesenchymal breast carcinomas assemble an immunosuppressive tumor microenvironment (TME) and mount refractory responses to immune checkpoint blockade (ICB). However, the precise mechanism(s) by which this occurs is unclear. Whether mesenchymal carcinoma cells express cell-intrinsic immunosuppressive factors that directly regulate the refractory responses of mesenchymal tumors to ICB is not known. For this reason, one goal of this proposal is to determine the identity and function of mesenchymal carcinoma cell-intrinsic factors in regulating immunosuppression and refractory responses to ICB. While my data demonstrate that only the tumors arising from mesenchymal, but not epithelial cell lines are enriched in immunosuppressive cells, the functional significance of these distinct subsets is unknown. Thus, another goal of this proposal is to determine whether immune infiltrates themselves are involved in the induction and/or maintenance of an immunosuppressive TME in the mesenchymal tumors. In addition to the aforementioned results, I made the striking observation that a small minority (~10%) of more mesenchymal cells could largely protect a majority (90%) of commingled epithelial carcinoma cells from elimination by anti-CTLA4. Thus, not only are mesenchymal carcinoma cells immunosuppressive, but they also protect their epithelial neighbors from immune attack. However, whether they do so by exerting immunosuppressive forces in a systemic (endocrine) fashion or localized (paracrine) fashion is unclear. Hence the final goal of this proposal is to explore how mesenchymal carcinoma cells protect epithelial cells residing within the same tumor from immune attack. The work proposed in this proposal is likely to uncover the molecular players and cellular subsets involved in inducing EMT-mediated immunosuppression. This study is expected to have an important positive impact through identifying novel diagnostic and prognostic markers of breast carcinomas that could potentially be used for immunotherapeutic intervention as well.