Principal Investigator: Anushka Dongre

DESCRIPTION (provided by applicant): 

The use of immune checkpoint blockade therapies has revolutionized cancer treatment, given its powers to create durable clinical responses. However, while melanomas and non-small cell lung cancers mount proficient responses to these therapies, the responsiveness of breast carcinomas has been largely limited. This provokes the question of whether the proportion of occasionally curative responses can be enhanced by improving current treatment regimens for breast carcinomas.

The epithelial-mesenchymal transition (EMT) is a cell-biological process that potentiates the aggressiveness of breast carcinomas and drives refractory responses to immunotherapies. Moreover, this program is a reversible process in which carcinoma cells residing in a more-mesenchymal state can lapse back to a more-epithelial state by undergoing a mesenchymal-to-epithelial transition (MET). This can be accomplished by inhibiting autocrine TGF-β1 signaling, which is critical for maintaining cancer cells in the mesenchymal state. Strikingly, TGF-β1 itself, is highly immunosuppressive and can directly blunt the cytolytic ability of anti-tumor immune cells, that can otherwise mount proficient anti-tumor responses. Thus, inhibiting TGF-β1 would represent an attractive strategy to not only reverse the EMT program, but also concomitantly reverse immune suppression within the tumor microenvironment. However, whether encouraging cancer cells to undergo an MET can subsequently sensitize them to various forms of immunotherapies is unknown. Thus, the premise of this proposal is to determine whether reversing the EMT program can enhance the susceptibility of breast tumors to immune checkpoint blockade therapies.