PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells

Gerlach K, Popp V, Wirtz S, Al-Saifi R, Gonzalez Acera M, Atreya R, Dregelis T, Vieth M, Fichtner-Feigl S, Mckenzie ANJ, Rosenbauer F, Weigmann B, Neurath M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Journal of Crohns & Colitis Elsevier

DOI: 10.1093/ecco-jcc/jjac097

Abstract

Background and Aims Colorectal cancer [CRC] is one of the most frequent malignancies, but the molecular mechanisms driving cancer growth are incompletely understood. We characterised the roles of the cytokine IL-9 and Th9 cells in regulating CRC development. Methods CRC patient samples and samples from AOM/DSS treated mice were analysed for expression of IL-9, CD3, and PU.1 by FACS analysis and immunohistochemistry. IL-9 citrine reporter mice, IL-9 knockout mice, and PU.1 and GATA3 CD4-Cre conditional knockout mice were studied in the AOM/DSS model. DNA minicircles or hyper-IL-6 were used for overexpression of cytokines in vivo. Effects of IL-6 and IL-9 were determined in organoid and T cell cultures. Claudin2/3 expression was studied by western blotting and bacterial translocation by FISH. Results We uncovered a significant expansion of IL-9- and PU.1-expressing mucosal Th9 cells in CRC patients, with particularly high levels in patients with colitis-associated neoplasias. PU.1(+) Th9 cells accumulated in experimental colorectal neoplasias. Deficiency of IL-9 or inactivation of PU.1 in T cells led to impaired tumour growth in vivo, suggesting a protumoral role of Th9 cells. In contrast, GATA3 inactivation did not affect Th9-mediated tumour growth. Mechanistically, IL-9 controls claudin2/3 expression and T cell-derived IL-6 production in colorectal tumours. IL-6 abrogated the anti-proliferative effects of IL-9 in epithelial organoids in vivo. IL-9-producing Th9 cells expand in CRC and control IL-6 production by T cells. Conclusions IL-9 is a crucial regulator of tumour growth in colitis-associated neoplasias and emerges as potential target for therapy.

Authors with CRIS profile

Katharina Gerlach Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Vanessa Popp Institute of Radiology Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Miguel Gonzalez Acera Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen Michael Vieth Professur für Allgemeine Pathologie am Medizincampus Oberfranken Benno Weigmann Medizinische Fakultät Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1)

Involved external institutions

Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) MRC Laboratory of Molecular Biology DE Germany (DE) Albert-Ludwigs-Universität Freiburg DE Germany (DE)

How to cite

APA:

Gerlach, K., Popp, V., Wirtz, S., Al-Saifi, R., Gonzalez Acera, M., Atreya, R.,... Neurath, M. (2022). PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells. Journal of Crohns & Colitis. https://doi.org/10.1093/ecco-jcc/jjac097

MLA:

Gerlach, Katharina, et al. "PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells." Journal of Crohns & Colitis (2022).

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