Suzuki, T. et al. (2023) β-catenin drives butyrophilin-like molecule loss and γδ T-cell exclusion in colon cancer. Cancer Immunology Research, 11(8), pp. 1137-1155. (doi: 10.1158/2326-6066.CIR-22-0644) (PMID:37309673) (PMCID:PMC10398359)
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Abstract
Intraepithelial lymphocytes (IELs) expressing γδ T-cell receptors (γδTCRs) 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. Re-expression of BTNL1 and BTNL6 in cancer cells increased γδIEL survival and activation in co-culture 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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by grants from Wellcome Trust (Seed Award 208990/Z/17/Z to SBC and Senior Clinical Research Fellowship 206314/Z/17/Z to SJL); Cancer Research UK Glasgow Centre (A25142 to SBC); Marie Skłodowska Curie Actions European Fellowship (GDCOLCA 800112 to TS); Naito Foundation Grant for Research Abroad (to TS); Medical Research Council (MR/R502327/1 to SBC & JE and MR/R502327/1 to JE); Greater Glasgow and Clyde endowment (306620-01 to JE); Cancer Research UK (Early Detection Project Grant A29834 to PD and Career Establishment Award RCCCEA-Nov21\100003 to SBC); Cancerfonden (CAN 2018/542 and 21 1572 Pj to CC); the Swedish Research Council, Vetenskapsrådet (2021-03075 to CC); Linköping University (CC); Knut and Alice Wallenberg Foundation (Wallenberg Molecular Medicine fellowship award to CC); and the NIH (R01DK121915 and R01CA190558 to MV). AH was supported by Cancer Research UK core funding at the Francis Crick Institute (FC001093). OJS and KB were supported by Cancer Research UK core funding at the Cancer Research UK Beatson Institute (A17196 and A31287). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Wiesheu, Robert and Gilroy, Dr Kathryn and Hayman, Ms Hannah-Louise and Georgakopoulou, Anastasia and Coffelt, Professor Seth and Roseweir, Dr Antonia and Gay, David and Blyth, Professor Karen and Yin Swe, Ms Kyi Lai and Edwards, Professor Joanne and Ridgway, Dr Rachel and Kilbey, Dr Anna and Sansom, Professor Owen |
| Authors: | Suzuki, T., Kilbey, A., Casa-Rodríguez, N., Lawlor, A., Georgakopoulou, A., Hayman, H.-L., Yin Swe, K. L., Nordin, A., Cantù, C., Vantourout, P., Ridgway, R. A., Byrne, R. M., Chen, L., Verzi, M. P., Gay, D. M., Vázquez, E. G., Belnoue-Davis, H. L., Gilroy, K., Kostner, A. H., Kersten, C., Thuwaj, 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., and Coffelt, S. B. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| Journal Name: | Cancer Immunology Research |
| Publisher: | American Association for Cancer Research |
| ISSN: | 2326-6066 |
| ISSN (Online): | 2326-6074 |
| Published Online: | 13 June 2023 |
| Copyright Holders: | Copyright © 2023 American Association for Cancer Research |
| First Published: | First published in Cancer Immunology Research 11(8): 1137-1155 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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