Colon cancers develop by stepwise accumulation of oncogenic mutations in epithelial stem cells. These mutated stem cells multiply by positive selection in healthy colon for years before transforming into cancers. In this proposal I aim to unravel an immune surveillance mechanism that prevents selection of mutated stem cells in healthy colon. Colon cancers with BRAFV600E mutation involve the proximal colon and disproportionately affect women above the age of 65 years. Based on the unique anatomic and demographic distribution of these cancers, I propose that BRAFV600E mutated stem cells have a strong selective advantage in the proximal colon. Regulatory T cells are part of the colonic stem cell microenvironment and, also heavily infiltrate BRAFV600E mutated cancers. Thus, I hypothesize that the regulatory T cells recognize and suppress the selection of BRAFV600E mutated stem cells in the healthy colon. To test this hypothesis, I have developed several genetically inducible lineage tracing mice that specifically induce BRAFV600E mutation in a single colonic stem cell. Using these mice, I will dissect the molecular mechanisms employed by regulatory T cells to perform surveillance against BRAFV600E mutated stem cells. Establishing the role of regulatory T cells in oncogene selection will lead to development of immune-prevention therapies against colon cancers. The proposal also includes a rigorous training program under the guidance of mentors with expertise in tumor immunology, stem cell biology and cancer evolution. Completion of the proposed activities will help me realize my goal of becoming an independent physician-scientist, investigating immune preventive strategies against colon cancer.