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 (Heisenberg-Professur) Michael Vieth Professur für Allgemeine Pathologie Benno Weigmann Medizinische Fakultät Markus Neurath Lehrstuhl für Innere Medizin I

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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