β-Catenin Drives Butyrophilin-like Molecule Loss and gd T-cell Exclusion in Colon Cancer

Abstract

Intraepithelial lymphocytes (IEL) expressing gd T-cell receptors gdTCR) play key roles in elimination of colon cancer. However, the recise mechanisms by which progressing cancer cells evade immuosurveillance by these innate T cells are unknown. Here, we nvestigated how loss of the Apc tumor suppressor in gut tissue ould enable nascent cancer cells to escape immunosurveillance by ytotoxic gdIELs. In contrast with healthy intestinal or colonic issue, we found that gdIELs were largely absent from the micronvironment of both mouse and human tumors, and that butyrphilin-like (BTNL) molecules, which can critically regulate gdIEL hrough direct gdTCR interactions, were also downregulated in umors. We then demonstrated that b-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased gdIEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of b-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant b-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and gd T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts gdIEL immunosurveillance and furthers cancer progression.