β-Catenin Promotes Colitis and Colon Cancer Through Imprinting of Proinflammatory Properties in T Cells

The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (T-regs) that naturally suppress inflammation is associated with longer patient survival. However, the role of T-regs in cancer remains controversial. We recently reported that T-regs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of ROR gamma t (retinoic acid-related orphan receptor-gamma t), the signature transcription factor of T(H)17 cells. We report that Wnt/beta-catenin signaling in T cells promotes expression of ROR gamma t. Expression of beta-catenin was elevated in T cells, including T-regs, of patients with colon cancer. Genetically engineered activation of beta-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including ROR gamma t, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of beta-catenin only in T-regs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/beta-catenin signaling in effector T cells and/or T-regs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.