β-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer
Issued Date
2023-08-03
Resource Type
eISSN
23266074
Scopus ID
2-s2.0-85166442008
Pubmed ID
37309673
Journal Title
Cancer immunology research
Volume
11
Issue
8
Start Page
1137
End Page
1155
Rights Holder(s)
SCOPUS
Bibliographic Citation
Cancer immunology research Vol.11 No.8 (2023) , 1137-1155
Suggested Citation
Suzuki T., Kilbey A., Casa-Rodríguez N., Lawlor A., Georgakopoulou A., Hayman H., Swe K.L.Y., Nordin A., Cantu C., Vantourout P., Ridgway R.A., Byrne R.M., Chen L., Verzi M.P., Gay D.M., Azquez E.G.V., Belnoue-Davis H.L., Gilroy K., Køstner A.H., Kersten C., Thuwajit C., Andersen D.K., Wiesheu R., Jandke A., Blyth K., Roseweir A.K., Leedham S.J., Dunne P.D., Edwards J., Hayday A., Sansom O.J., Coffelt S.B. β-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer. Cancer immunology research Vol.11 No.8 (2023) , 1137-1155. 1155. doi:10.1158/2326-6066.CIR-22-0644 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/88284
Title
β-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer
Author(s)
Suzuki T.
Kilbey A.
Casa-Rodríguez N.
Lawlor A.
Georgakopoulou A.
Hayman H.
Swe K.L.Y.
Nordin A.
Cantu C.
Vantourout P.
Ridgway R.A.
Byrne R.M.
Chen L.
Verzi M.P.
Gay D.M.
Azquez E.G.V.
Belnoue-Davis H.L.
Gilroy K.
Køstner A.H.
Kersten C.
Thuwajit C.
Andersen D.K.
Wiesheu R.
Jandke A.
Blyth K.
Roseweir A.K.
Leedham S.J.
Dunne P.D.
Edwards J.
Hayday A.
Sansom O.J.
Coffelt S.B.
Kilbey A.
Casa-Rodríguez N.
Lawlor A.
Georgakopoulou A.
Hayman H.
Swe K.L.Y.
Nordin A.
Cantu C.
Vantourout P.
Ridgway R.A.
Byrne R.M.
Chen L.
Verzi M.P.
Gay D.M.
Azquez E.G.V.
Belnoue-Davis H.L.
Gilroy K.
Køstner A.H.
Kersten C.
Thuwajit C.
Andersen D.K.
Wiesheu R.
Jandke A.
Blyth K.
Roseweir A.K.
Leedham S.J.
Dunne P.D.
Edwards J.
Hayday A.
Sansom O.J.
Coffelt S.B.
Author's Affiliation
Siriraj Hospital
Faculty of Life Sciences & Medicine
School of Medicine, Dentistry & Nursing
Department of Genetics
The Francis Crick Institute
Akershus University Hospital
Beatson Institute for Cancer Research
School of Medicine, Dentistry and Biomedical Sciences
Linköpings Universitet
Nuffield Department of Medicine
University of Glasgow
Southern Hospital Trust
Faculty of Life Sciences & Medicine
School of Medicine, Dentistry & Nursing
Department of Genetics
The Francis Crick Institute
Akershus University Hospital
Beatson Institute for Cancer Research
School of Medicine, Dentistry and Biomedical Sciences
Linköpings Universitet
Nuffield Department of Medicine
University of Glasgow
Southern Hospital Trust
Other Contributor(s)
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.