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1038 T cell factor 1 (TCF-1) is a molecular checkpoint in colorectal carcinoma γδ T cell immunity
  1. Marina Yakou1,
  2. Sonia Ghilas1,
  3. Kelly Tran1,
  4. Yang Liao1,
  5. Shoukat Afshar-Sterle1,
  6. Anita Kumari1,
  7. Kevin Schmid1,
  8. Christine Dijkstra1,
  9. Chantelle Inguanti1,
  10. Simone Ostrouska1,
  11. Jordan Wilcox1,
  12. Maxine Smith2,
  13. Pavitha Parathan1,
  14. Amr Allam1,
  15. Hai-Hui Xue3,
  16. Gabrielle Belz4,
  17. Andreas Behren1,
  18. John Mariadason1,
  19. Grant Drummond5,
  20. Roland Ruscher2,
  21. David Williams6,
  22. Bhupinder Pal1,
  23. Wei Shi1,
  24. Matthias Ernst1,
  25. Dinesh Raghu1 and
  26. Lisa A Mielke1
  1. 1Olivia Newton-John Cancer Research Institute and La Trobe University, Heidelberg, VIC, Australia
  2. 2Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
  3. 3University of Iowa, Iowa City, IA, USA
  4. 4The University of Queensland, Brisbane, QLD, Australia
  5. 5Centre for Cardiovascular Biology and Disease Research, La Trobe University, Bundoora, VIC, Australia
  6. 6Department of Anatomical Pathology, Austin Health, Heidelberg, VIC, Australia
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Intraepithelial lymphocytes (IELs), including αβ and γδ T cells (T-IELs) constantly survey and play a critical role in maintaining the gastrointestinal (GI) epithelium. Recent reports highlight a critical function for γδ T-IELs in defense again colorectal carcinoma (CRC).1–3

Methods Tumor biopsies from patients with stage III CRC were analysed by multiplex immunohistochemistry to investigate immune cell location and immune cell phenotypes were correlated with patient outcome data. We used mouse models, flow cytometry and single cell RNA sequencing to analyse T-IELs in different regions of the gastrointestinal tract. In addition, targeted deletion of transcriptional regulators in γδ T-IELs was used to interrogate the function of γδ T-IELs in controlling tumor growth.

Results We show that cytotoxic molecules important for defense against cancer, were highly expressed by T-IELs in the small intestine. In contrast, abundance of colonic T-IELs was dependent on the microbiome, displayed higher expression of TCF-1/TCF7 and a reduced effector and cytotoxic profile, including low expression of granzymes. Targeted deletion of TCF-1 in γδ T-IELs induced a unique T-IEL effector profile and reduced colon tumor formation in mice. Finally, TCF-1 expression was significantly reduced in γδ T-IELs present in human CRCs compared to normal healthy colon, which strongly correlated with an enhanced γδ T-IEL effector phenotype and improved patient survival.

Conclusions Our findings highlight the exciting potential for exploiting colon-resident T cells subsets, including γδ T-IELs in the development of new immunotherapy strategies to treat CRC.


  1. Dasgupta S, Liu H, Bailey B, Wyrick C, Grieves J, DeBoever C, et al. gammadelta T Cells Control Gut Pathology in a Chronic Inflammatory Model of Colorectal Cancer. Cell Mol Gastroenterol Hepatol. 2021;12(3):1163–5 e8.

  2. de Vries NL, van de Haar J, Veninga V, Chalabi M, Ijsselsteijn ME, van der Ploeg M, et al. gammadelta T cells are effectors of immunotherapy in cancers with HLA class I defects. Nature. 2023;613(7945):743–50.

  3. Reis BS, Darcy PW, Khan IZ, Moon CS, Kornberg AE, Schneider VS, et al. TCR-Vgammadelta usage distinguishes protumor from antitumor intestinal gammadelta T cell subsets. Science. 2022;377(6603):276–84.

Ethics Approval Use of human samples were approved by the Austin Health Human Ethics Committee (Heidelberg, Australia protocol H2013/05077). Informed consent was obtained from all patients. All mice used in accordance with Austin Health Animal Ethics Committee or the James Cook University Animal Ethics Committee, Australia.

Consent None of the patient data in this abstract is identifiable.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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