Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer

Amicarella, F; Muraro, M G; Hirt, C; Cremonesi, E; Padovan, Elisabetta; Mele, V; Governa, V; Han, J; Huber, X; Droeser, R A; Zuber, M; Adamina, M; Bolli, M; Rosso, R; Lugli, Alessandro; Zlobec, Inti; Terracciano, Luigi; Tornillo, L; Zajac, P; Eppenberger-Castori, S; ... (2015). Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Gut, 66(4), pp. 692-704. BMJ Publishing Group 10.1136/gutjnl-2015-310016

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BACKGROUND The immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated. OBJECTIVE To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells. METHODS IL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments. RESULTS IL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival. CONCLUSIONS Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Padovan, Elisabetta; Lugli, Alessandro; Zlobec, Inti and Terracciano, Luigi

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0017-5749

Publisher:

BMJ Publishing Group

Language:

English

Submitter:

Doris Haefelin

Date Deposited:

18 Jan 2016 13:53

Last Modified:

19 Mar 2017 02:05

Publisher DOI:

10.1136/gutjnl-2015-310016

PubMed ID:

26719303

Uncontrolled Keywords:

Cancer Immunobiology; Colorectal Cancer; Immune Response; Inflammatory Mediators; T Lymphocytes

BORIS DOI:

10.7892/boris.74595

URI:

https://boris.unibe.ch/id/eprint/74595

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