Project Summary Colon cancer remains the 3rd most commonly diagnosed cancer and the 3rd highest cancer related mortalities in both men and women. Tumors are often resected, but there are less treatment options available for those diagnosed in later stages. Immunotherapy has had mixed results in colon cancer and thus, new therapeutic strategies are needed to improve outcome for particularly late stage patients. We have been examining mucosal associated invariant T (MAIT) cells as a subset of T cells that display innate effector qualities, with the potential to be harnessed as HLA-independent immunotherapeutic agents. We have found that MAIT cells have the potential to decrease tumor growth and have identified a potential mechanism by which MAIT cells enhance innate immune cell responses in order to promote anti-tumor immunity. Based on our novel preliminary data, we propose to test the hypothesis that MAIT cells have the capacity for anti-tumor effects, through both direct cytotoxicity in a T cell receptor-dependent manner, and indirect mechanisms through the recruitment of innate immune cells. To test this hypothesis, we propose carefully designed experiments to examine the potential of MAIT cells for therapeutic potential using primary human cells in organoid models and mouse tumors in therapeutic approaches in preclinical models. Furthermore, we will test this therapeutic approach in combination with checkpoint therapy to enhance anti- tumor cytotoxic activity. Data collected for this project could lead to a novel immunotherapy approach for gastrointestinal cancers.

Project Narrative New approaches for colon cancer treatments are needed to improve patient outcomes, particularly in advanced stage disease. In this study, we propose to investigate the potential of mucosal-associated invariant T (MAIT) cells to activate anti-tumor immunity and their potential as a therapeutic approach that could be combined with checkpoint therapy to combat colon cancer.