Article Text

PDF
Original article
Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer
  1. Elise Punkenburg1,2,
  2. Tina Vogler1,2,
  3. Maike Büttner3,
  4. Kerstin Amann3,
  5. Max Waldner1,
  6. Raja Atreya1,
  7. Benjamin Abendroth1,2,
  8. Jonas Mudter6,
  9. Susanne Merkel4,
  10. Eike Gallmeier7,
  11. Stefan Rose-John5,
  12. Markus F Neurath1,
  13. Kai Hildner1,2
  1. 1Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany
  2. 2Max Eder Research Group supported by the German Cancer Aid, University Hospital Erlangen, Erlangen, Germany
  3. 3Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Erlangen, Germany
  4. 4Department of Surgery, University Hospital, Erlangen, Germany
  5. 5Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
  6. 6Medical Department, Hospital Ostholstein, Eutin, Germany
  7. 7Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University of Marburg, Marburg, Germany
  1. Correspondence to Professor Kai Hildner, Department of Medicine 1, University Hospital Erlangen, Ulmenweg 18, Erlangen D-91054, Germany; Kai.Hildner{at}uk-erlangen.de

Abstract

Objectives IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17-associated transcription factors in sporadic and colitis-associated colon cancer in vivo.

Design We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and RORγt in patients with IBD and CRC.

Results Batf but not retinoic acid-related orphan receptor γt(RORγt) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn's disease (CD) tissue samples. In CRC also Batf but not RORγt expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not RORγt was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4+ T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation-induced CRC. Colitis-associated Batf−/− tumours lacked IL-17a+IL-23R+IL-6+CD4+ T cells, hence displaying characteristics reminiscent of human CRC-infiltrating CD4+ T cells. Strikingly, Batf−/− tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor.

Conclusions Batf-dependent IL-23R+IL-6+CD4+ Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R+ T cells represent a potential future therapeutic target limiting CRC progression.

  • COLORECTAL CANCER
  • INFLAMMATORY BOWEL DISEASE
  • T LYMPHOCYTES
  • INTERLEUKINS
  • INFLAMMATION

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.