Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Issue 4 (30th December 2015)

• Record Type: Journal Article
• Authors: Amicarella, F; Muraro, M G; Hirt, C; Cremonesi, E; Padovan, E; Mele, V; Governa, V; Han, J; Huber, X; Droeser, R A; Zuber, M; Adamina, M; Bolli, M; Rosso, R; Lugli, A; Zlobec, I; Terracciano, L; Tornillo, L; Zajac, P; Eppenberger-Castori, S; Trapani, F; Oertli, D; Iezzi, G
• Is Part Of: Gut. Volume 66:Issue 4(2017)
• Page Start: 692
• Page End: 704
• Publication Date: 2015-12-30
• Subjects: COLORECTAL CANCER -- T LYMPHOCYTES -- CANCER IMMUNOBIOLOGY -- IMMUNE RESPONSE -- INFLAMMATORY MEDIATORS; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2015-310016
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.