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Figure S5 from β-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer

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posted on 2023-08-03, 08:20 authored by Toshiyasu Suzuki, Anna Kilbey, Nuria Casa-Rodríguez, Amy Lawlor, Anastasia Georgakopoulou, Hannah Hayman, Kyi Lai Yin Swe, Anna Nordin, Claudio Cantù, Pierre Vantourout, Rachel A. Ridgway, Ryan M. Byrne, Lei Chen, Michael P. Verzi, David M. Gay, Ester Gil Vázquez, Hayley L. Belnoue-Davis, Kathryn Gilroy, Anne Helene Køstner, Christian Kersten, Chanitra Thuwajit, Ditte K. Andersen, Robert Wiesheu, Anett Jandke, Karen Blyth, Antonia K. Roseweir, Simon J. Leedham, Philip D. Dunne, Joanne Edwards, Adrian Hayday, Owen J. Sansom, Seth B. Coffelt

Disruption of WNT gradient in normal intestinal villi reduces gamma delta T cells

Funding

Wellcome Trust (WT)

Cancer Research UK (CRUK)

HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA)

Naito Foundation (内藤記念科学振興財団)

Medical Research Council (MRC)

NHS Greater Glasgow and Clyde

Cancerfonden (Swedish Cancer Society)

Vetenskapsrådet (VR)

Linköpings Universitet (LiU)

Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

United States Department of Health and Human Services

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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History

ARTICLE ABSTRACT

Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) 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 γδIELs. In contrast with healthy intestinal or colonic tissue, we found that γδIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR interactions, were also downregulated in tumors. We then demonstrated that β-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 γδIEL 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 β-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant β-catenin mouse models restored Hnf4a, Hnf4g, and Btnl 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.

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    Cancer Immunology Research

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    Keywords

    cancer

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