Elise Punkenburg1, Tina Vogler1, Maike Büttner2, Kerstin Amann2, Max Waldner3, Raja Atreya3, Benjamin Abendroth1, Jonas Mudter4, Susanne Merkel5, Eike Gallmeier6, Stefan Rose-John7, Markus F Neurath3, Kai Hildner1. 1. Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany Max Eder Research Group supported by the German Cancer Aid, University Hospital Erlangen, Erlangen, Germany. 2. Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Erlangen, Germany. 3. Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany. 4. Medical Department, Hospital Ostholstein, Eutin, Germany. 5. Department of Surgery, University Hospital, Erlangen, Germany. 6. Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University of Marburg, Marburg, Germany. 7. Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Entities:
Keywords:
COLORECTAL CANCER; INFLAMMATION; INFLAMMATORY BOWEL DISEASE; INTERLEUKINS; T LYMPHOCYTES
Authors: Y Lin; L Cheng; Y Liu; Y Wang; Q Wang; H L Wang; G Shi; J S Li; Q N Wang; Q M Yang; S Chen; X L Su; Y Yang; M Jiang; X Hu; P Fan; C Fang; Z G Zhou; L Dai; H X Deng Journal: Mucosal Immunol Date: 2020-05-28 Impact factor: 7.313
Authors: Evelyn Ullrich; Benjamin Abendroth; Johanna Rothamer; Carina Huber; Maike Büttner-Herold; Vera Buchele; Tina Vogler; Thomas Longerich; Sebastian Zundler; Simon Völkl; Andreas Beilhack; Stefan Rose-John; Stefan Wirtz; Georg F Weber; Sakhila Ghimire; Marina Kreutz; Ernst Holler; Andreas Mackensen; Markus F Neurath; Kai Hildner Journal: J Clin Invest Date: 2018-01-29 Impact factor: 14.808