| First Author | Suzuki T | Year | 2023 |
| Journal | Cancer Immunol Res | Volume | 11 |
| Issue | 8 | Pages | 1137-1155 |
| PubMed ID | 37309673 | Mgi Jnum | J:360727 |
| Mgi Id | MGI:7850872 | Doi | 10.1158/2326-6066.CIR-22-0644 |
| Citation | Suzuki T, et al. (2023) beta-Catenin Drives Butyrophilin-like Molecule Loss and gammadelta T-cell Exclusion in Colon Cancer. Cancer Immunol Res 11(8):1137-1155 |
| abstractText | Intraepithelial lymphocytes (IEL) expressing gammadelta T-cell receptors (gammadeltaTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic gammadeltaIELs. In contrast with healthy intestinal or colonic tissue, we found that gammadeltaIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate gammadeltaIEL through direct gammadeltaTCR interactions, were also downregulated in tumors. We then demonstrated that beta-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 gammadeltaIEL 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 beta-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant beta-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and gammadelta T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts gammadeltaIEL immunosurveillance and furthers cancer progression. |
