The Mechanistic Underpinnings of Epithelial-Mesenchymal Transition (EMT) and CD73-Mediated Immunosuppression in Breast Carcinomas
Principal Investigator: Anushka Dongre
DESCRIPTION (provided by applicant):
Epithelial-to-mesenchymal transition (EMT), which potentiates the aggressive properties of breast carcinomas, also makes them refractory to cancer immunotherapy. Importantly, abrogating CD73 (an ectoenzyme that generates immunosuppressive adenosine) from more-mesenchymal breast cancer cells, can completely sensitize them to immunotherapy. However, the underlying mechanism(s) of sensitization remains elusive. Moreover, the regulatory networks that control the expression of CD73 in breast cancer cells are not well understood. Hypothesis: We hypothesize that abrogation of CD73 from more-mesenchymal tumors promotes the formation of anti-tumor CD4+ helper-T-cells that sensitizes them to immunotherapy. Moreover, the expression of CD73 itself, is directly regulated by activation of the EMT program in breast cancer cells. Specific Aims: In the First Aim, we will determine the identities of CD4+ T-cell subsets present in mesenchymal tumors lacking CD73. We will also assess their functional relevance in sensitizing these tumors to immunotherapy. In the Second Aim, we will determine whether altering the epithelial - mesenchymal phenotypic plasticity of breast cancer cells can regulate CD73 expression. Methodology: In Aim 1, we will use novel, pre-clinical mouse models of more-mesenchymal breast tumors together with adoptive transfer techniques, flow cytometry, and fluorescent imaging. In Aim 2, we will activate the EMT program in human breast cancer cells by doxycycline-induced expression of various EMT-inducing transcription factors. Impact: Triple negative breast cancers activate components of the EMT program and mount low objective responsive rates to immunotherapy (5-23%). The expression of CD73 has also been identified as a poor prognosis factor for breast cancer patients. Targeting CD73 in breast cancer cells that have activated the EMT program, will help potentiate the responses of breast tumors to immunotherapies. Thus, this proposal will address the coalition research goal of curing breast cancer.