Characterization of the phenotypic plasticity of IL17-producing T cells during colorectal cancer development and their interactions with the microbiome

A dynamic molecular dialogue between microbiota and host ensures that gastrointestinal tract colonization occurs as a state of mutualism preventing inflammation. Breakdown of this homeostasis can result in IBD, but may also potentiate colorectal cancer (CRC). Studies show that both IBD and CRC are associated to a degree of inflammation by increased production of IL17. T cells with IL17-producing potential co-develop with the microbiota upon colonization at birth and are crucial to avoid inflammation. Initially, these cells exist in a regulatory state and do not produce IL17, but studies have shown that the cells can plastically change and increase the production of IL17 which is directly linked to inflammation and CRC. Therefore, we hypothesize that during polyp and CRC development these microbiome-specific T cells change their levels of IL17 production directly by interacting with the bacteria. To test this, we will first build a tool to check reactivity of T cell receptors to microbial proteins. We will deeply characterize healthy, polyp and tumor tissue from CRC resection specimens deeply focusing on T cells with IL17-producing potential. We will test whether these T cells react to the patient’s microbiome. Lastly, we will more in depth focus on the mechanisms of IL17 production plasticity and validate hypotheses in a larger cohort. This project may provide key insight on gut homeostasis and deviations, thus pinpointing novel therapies to overcome these.