Abstract A82: Direct and indirect regulators of epithelial-to-mesenchymal transition mediated immunosuppression in breast carcinomas

Abstract

Abstract The epithelial-to-mesenchymal transition (EMT) is a cell-biologic program that confers mesenchymal traits on carcinoma cells and drives their metastatic dissemination. We recently demonstrated that epithelial and mesenchymal carcinomas recruit distinct immune cells to their tumor microenvironments (TME) and differ in their susceptibility to checkpoint blockade. Specifically, mesenchymal tumors recruit immunosuppressive cells to their TME and are refractory to checkpoint blockade, while epithelial tumors recruit CD8+ T cells instead and are sensitive to checkpoint blockade. The mechanism(s) underlying such EMT-mediated immunosuppression remains elusive. Furthermore, the biologic relevance of various immune cells infiltrating epithelial versus mesenchymal tumors requires further understanding. Using a combination of novel epithelial and mesenchymal tumor models arising in syngeneic immunocompetent hosts combined with transcriptomic approaches, we demonstrate that mesenchymal but not epithelial tumors are specifically associated with an immunosuppressive gene signature. Furthermore, while CD8+ T cells play a critical role in regulating tumor progression and responses to checkpoint blockade in epithelial breast tumors, they do not do so in mesenchymal breast tumors. On the contrary, mesenchymal tumors recruit and rely on M2-macrophages to generate an immunosuppressive TME and mount refractory responses to checkpoint blockade. Finally, we demonstrate that mesenchymal tumors utilize a combination of carcinoma cell-intrinsic direct and indirect mechanism(s) to assemble an immunosuppressive TME. This work suggests that epithelial and mesenchymal breast carcinomas have dramatically different immunologic profiles. Thus, the residence of carcinoma cells in the epithelial or mesenchymal states can dictate their corresponding responses to checkpoint blockade immunotherapies. This in turn can therefore have a direct translational impact on breast cancer patients. Citation Format: Anushka Dongre, Mohammad Rashidian, Elinor Ng Eaton, Ferenc Reinhardt, Sunita Nepal, Hidde Ploegh, Robert Weinberg. Direct and indirect regulators of epithelial-to-mesenchymal transition mediated immunosuppression in breast carcinomas [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A82.