The ASPIRE Path in Molecular Medicine

Despite improvements in response brought on by the addition of immune checkpoint blockade, many triple-negative breast cancer patients continue to demonstrate resistance to treatment. Decreased MHC-I expression is extremely common in the tumor microenvironment (TME) and has been associated with lessened response to ICB across multiple tumor subtypes due to its role in antigen presentation and T cell activation. My research focuses on an emerging group of drugs, diacylglycerol kinase inhibitors (DGKis), which increase T cell signaling downstream of diacylglycerol and help overcome decreased T cell activation in the TME. Using a miRNA-based silencing system to titrate MHC-I expression, ‘miSFITs’, we aim to discover the threshold at which decreased tumor-specific MHC-I expression begins to affect a-PD-1 therapeutic outcomes and assess the impact of DGKi therapy in rescuing decreased ICB response resulting from decreased MHC-I expression. Additionally, we will evaluate the impact of DGKis on the risk of developing immune-related adverse events associated with ICB. The primary objective of this project is to identify the impact of decreased tumor-specific MHC-I expression on immunologic phenotypes, ICB response, and how to therapeutically overcome these barriers to improve patient responses.