(506) An intestinal TH17 cell-derived subset can initiate cancer

Introduction/Rationale: Approximately 25% of cancers are preceded by chronic inflammation occurring at the site of tumor development. This inflammation is established long before any sign of transformation is detected, and it likely involves several actors, including immune cells. However, whether it can be initiated by a specific immune cell population is unknown. Identifying such a population and the factors controlling its development is essential for our understanding of the early steps of cancer development and for the development of prophylactic therapies.

Methods: The Transforming Growth Factor-β (TGF-β) and the T helper 17 lymphocytes (Th17) cells are 2 main actors of the intestinal inflammation. The development of Th17 is largely impacted by TGF-β, but how its impact the biology of already differentiated Th17 cells and how its shape their behavior during chronic inflammation is unknown. We used the Cre-Lox system to generate original mice models allowing to delete or over-express the TGF-β signaling pathway in already differentiated Th17 cells.

Results: We unveil that the non-canonical TGF-β signaling pathway in Th17 cells is required to maintain their expression of ROR-t and to repress the transcription factor KLF6. In absence of TGF-β signaling, KLF6 promotes the expression of T-bet and the acquisition of a “Th1-like” phenotype. Those cells become tumorigenic by reacting against the gut microbiota, causing a strong IFN-but not IL-17A mediated inflammation, which lead to the development of adenocarcinoma.

Conclusion: We identify a Th17 cell subpopulation that can initiate chronic inflammation in the gut, leading to adenocarcinoma. This tumorigenic subset develops from a pre-tumorigenic Th17 cell population present at steady state in the intestine. The switch from pre-tumorigenic to a tumorigenic stage is promoted by KLF6 and controlled by the TGF-β signaling on already differentiated Th17 cells.