title: Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer.
abstract: 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.
  
  
  
  To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Amicarella
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.
authors.forename: M G
authors.initials: MG
authors.lastname: Muraro
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Hirt
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Cremonesi
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Padovan
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Mele
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.|Institute of Pathology, University of Basel, Basel, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Governa
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.|Department of General Surgery, Shanghai East Hospital, Tongji University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.|Department of General Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: X
authors.initials: X
authors.lastname: Huber
authors.affiliation: Department of General Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: R A
authors.initials: RA
authors.lastname: Droeser
authors.affiliation: Department of Visceral Surgery, Kantonsspital Olten, Olten, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Zuber
authors.affiliation: Department of Visceral Surgery, Kantonsspital St Gallen, St. Gallen, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Adamina
authors.affiliation: Department of Visceral Surgery, St Claraspital, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Bolli
authors.affiliation: Department of Visceral Surgery, Ospedale Civico Lugano, Lugano, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Rosso
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Lugli
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Zlobec
authors.affiliation: Institute of Pathology, University of Basel, Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Institute of Pathology, University of Basel, Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Tornillo
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Zajac
authors.affiliation: Institute of Pathology, University of Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Eppenberger-Castori
authors.affiliation: Institute of Pathology, University of Basel, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Trapani
authors.affiliation: Department of General Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Oertli
authors.affiliation: Department of Biomedicine, Institute of Surgical Research, University of Basel, Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Iezzi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054418:Chemokine CCL20 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000235:genetics; D054370:Chemokine CXCL9 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D020381:Interleukin-17 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000737:chemistry / Q000201:enzymology / Q000276:immunology; D009195:Peroxidase / Q000032:analysis; D010641:Phenotype; D011379:Prognosis; D017452:Receptors, IgG / Q000032:analysis; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D058504:Th17 Cells / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*
chemical_list: C108355:CCL20 protein, human; C483024:CCL5 protein, human; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054418:Chemokine CCL20; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D020381:Interleukin-17; D016209:Interleukin-8; D017452:Receptors, IgG; D009195:Peroxidase
keywords: CANCER IMMUNOBIOLOGY; COLORECTAL CANCER; IMMUNE RESPONSE; INFLAMMATORY MEDIATORS; T LYMPHOCYTES