Colorectal cancer (CRC) remains the third most common cause of cancer-related deaths in the U.S. The majority (~85%) of CRC tumors are non-immunogenic, i.e. they lack a significant number of infiltrating T cells, and are typically unresponsive to the immune-checkpoint inhibitor based therapies that have dramatically changed the way we treat many cancer patients. T cells isolated from non-immunogenic, microsatellite stable (MSS) CRC have lower levels of the CD28 protein, which provides a co-stimulatory signal required for T cell activation, trafficking, proliferation, differentiation and cytotoxic activity. We are testing the following hypothesis that extracellular vesicles (EVs) containing immunosuppressive microRNAs secreted by CRC cells suppress host T cell activity locally and in tumor draining lymph nodes, resulting in a deficient immune response that allows for increased tumor progression and growth. Results from this study will fundamentally advance our knowledge of how cancer cells modulate and suppress the immune response, provide novel targets, and form the basis for a new anti-cancer therapeutic strategy.