Immune Control of Oncogene Selection in the Colon.

Crypt fixation is an early and essential event of colorectal cancer initiation 1–6. It is an evolutionary process where precancerous stem cells compete with their healthy neighbors for monoclonal fixation of intestinal crypts 1–6. This competition involves stochastic interaction between three cell populations, oncogene mutant clones, competing wild-type clones and the cells populating their microenvironment. Interactions between competing WT and mutant clones are well studied; however, the impact of the microenvironment cells on crypt fixation, has been challenging to quantify 1–6. This is due to the absence of suitable experimental and theoretical models to study three-way stochastic interactions between competing clones and cells in their microenvironment. To overcome this challenge, we integrated established mosaic clonal selection models1,7,8 and immune depletion models9 with the theoretical framework provided by Stochastic Conveyor Belt model 10,11. Using this approach, we quantified the selective advantage of colonic stem cells with the BRAFV600E mutation, one of the most prevalent human oncogenes. We showed that BRAFV600E confers a selective advantage to colonic stem cells but approximately half of the clones are destined for clonal extinction. We show mechanistically that clonal extinction of these precancerous cells is actively mediated by adaptive immune system. Specific depletion of regulatory T cells or targeted deletion of Major Histocompatibility Complex Class II (MHCII) or interleukin 10 receptor A (IL10RA) on the BRAFV600E mutated clones, prevented their extinction. Overall, these findings reveal a new immune sensing mechanism whereby Tregs recognize and eliminate precancerous stem cells before malignant transformation. Understanding this interplay between microenvironment and stem cell dynamics at tumor initiation will enable the development of immunoprevention strategies against colon cancer initiation, rather than treat existing tumors. *Birgit Tschiatschek & Miraal Maqsood contributed equally.