β-catenin promotes colitis and colon cancer through imprinting of pro-inflammatory properties in T-cells. (LYM3P.727)

Abstract

Abstract The density and type of lymphocytes infiltrating colon tumors are predictive of the clinical outcome of colon cancer. High densities of TH17 cells and inflammation predict poor outcome, while infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We previously reported that Tregs in colon cancer patients can become pro-inflammatory and tumor promoting. These properties were directly linked with their expression of RORγt, the signature transcription factor of TH17 cells. Here, we report that Wnt/β-catenin signaling in T-cells promotes expression of RORγt. Expression of β-catenin was elevated in T-cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T-cells resulted in enhanced chromatin accessibility in the proximity of Tcf-1 binding sites genome-wide, induced expression of TH17 signature genes including RORγt, and promoted TH17-mediated inflammation. Strikingly, the mice had inflammation of small-intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. Based on these findings we conclude that activation of Wnt/β-catenin signaling in effector T-cells and/or Tregs is causatively linked with the imprinting of pro-inflammatory properties and promotion of colon cancer.