Project Summary: Colorectal cancer (CRC) accounts for nearly 10% of all cancer diagnoses in the VA system1. Additionally, the VA system treats 3% of the total number of US cases of CRC and 6% of all US cases in males2. The immune response to CRC is critical to therapeutic response and survival. Cytotoxic T cells (CTL) are the end mediators of the anti-tumor response. As expected, tumor associated CTL are also associated with treatment response and survival in CRC. In our murine model of colorectal cancer, we have found that depending on the therapeutic regimen used, there is a differential effect on the number and type of CTL in the tumor microenvironment. FOLFOX chemotherapy, the first-line chemotherapeutic regimen in CRC, controls tumor growth better than individual arms alone and engenders increased antigen specific CTL in the tumor microenvironment. Our understanding of how FOLFOX chemotherapy affects tumor associated CTL type and response is unknown. This information is critical for the future design of clinical trials testing novel therapeutic combinations in CRC. In this VA CDA-2 proposal, we will study the differential effect of FOLFOX chemotherapy on CTL type, function, signaling, exhaustion, and memory. Additionally, we will test the effect of innate immune sensing to induce CTL and work in combination with FOLFOX in CRC. A multi-disciplinary team of VA Merit and NIH-R01 funded clinician-scientists and basic scientists have been recruited to comprise a mentorship team designed to ensure the success of the application candidate. The data and skill development outlined in this proposal will ensure the development of a successful research career for the candidate and pre-clinical data in support of future clinical trials in CRC utilizing immune based therapy in combination chemotherapy.