{"doi":"10.1101/2022.06.10.495115","title":"β-catenin obstructs γδ T cell immunosurveillance in colon cancer through loss of BTNL expression","abstract":"ABSTRACT WNT/β-catenin signaling endows cancer cells with proliferative capacity and immune-evasive functions that impair anti-cancer immunosurveillance by conventional, cytoxtoic T cells. However, the impact of dysregulated WNT signalling on unconventional, tissue-resident T cells, specifically in colon cancer is unknown. Here, we show that cancer cells in Apc -mutant mouse models escape immunosurveillance from gut-resident intraepithelial lymphocytes (IELs) expressing γδ T cell receptors (γδTCRs). Analysis of late-stage tumors from mice and humans revealed that γδIELs are largely absent from the tumor microenvironment, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR-interactions, are also downregulated. We could attribute this to β-catenin stabilization, which rapidly decreased expression of the transcription factors, HNF4A and HNF4G, that we found to bind promoter regions of Btnl genes, thereby driving their expression in normal gut epithelial cells. Indeed, inhibition of β-catenin signaling restored Btnl1 gene expression and γδ T cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts γδIEL immunosurveillance and furthers cancer progression.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":309266,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9417,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1004290,"name":"Anna Kilbey","orcid":"0000-0002-7806-2514","position":1,"is_corresponding":false},{"id":65387,"name":"Rachel A. 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Belnoue-Davis","orcid":"0000-0003-2914-4932","position":11,"is_corresponding":false},{"id":65374,"name":"Kathryn Gilroy","orcid":"0000-0003-4607-194X","position":12,"is_corresponding":false},{"id":1004295,"name":"Anne Helene Køstner","orcid":"0000-0002-9489-9461","position":13,"is_corresponding":false},{"id":1004296,"name":"Christian Kersten","orcid":"0000-0002-5691-2944","position":14,"is_corresponding":false},{"id":1004297,"name":"Chanitra Thuwajit","orcid":"0000-0001-9506-6405","position":15,"is_corresponding":false},{"id":1004298,"name":"Ditte K. 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