Epithelial-mesenchymal plasticity and immunosuppression in canine carcinomas reveals cross-species upregulation of CD109.

Abstract

Epithelial-mesenchymal plasticity (EMP) is activated in carcinoma cells to drive metastasis and chemoresistance. Recently, we demonstrated that EMP activation results in an immunosuppressive tumor microenvironment and immunotherapy resistance in a syngeneic orthotopic murine model. However, it has yet to be shown whether this is conserved in canine carcinomas. Here, we show that in spontaneous canine mammary carcinomas (CMCs), which share clinical and molecular features with human breast cancers, EMP is linked to the recruitment of immunosuppressive cells. Additionally, we identify that the glycoprotein CD109 is associated with EMP-mediated immunosuppression in canine, murine, and human models. CD109 has been associated with tumorigenicity, but not immunosuppression in cancers of any species. Finally, we identified shared upregulation of immunosuppressive factors across multiple canine carcinomas, including oral squamous cell carcinoma, urothelial carcinoma, and pulmonary carcinoma. These findings demonstrate that EMP is associated with immunosuppression in canine carcinomas, with translational implications for human breast cancers.