title: Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments.
abstract: Th17 cells play an active role in autoimmune diseases. However, the nature of Th17 cells is poorly understood in cancer patients. We studied Th17 cells, the associated mechanisms, and clinical significance in 201 ovarian cancer patients. Tumor-infiltrating Th17 cells exhibit a polyfunctional effector T-cell phenotype, are positively associated with effector cells, and are negatively associated with tumor-infiltrating regulatory T cells. Tumor-associated macrophages promote Th17 cells through interleukin-1beta (IL-1beta), whereas tumor-infiltrating regulatory T cells inhibit Th17 cells through an adenosinergic pathway. Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome. Altogether, Th17 cells may contribute to protective human tumor immunity through inducing Th1-type chemokines and recruiting effector cells to the tumor microenvironment. Inhibition of Th17 cells represents a novel immune evasion mechanism. This study thus provides scientific and clinical rationale for developing novel immune-boosting strategies based on promoting the Th17 cell population in cancer patients.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI 48109-0669, USA. ilonak@med.umich.edu
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.forename: Mousumi
authors.initials: M
authors.lastname: Banerjee
authors.forename: Pui
authors.initials: P
authors.lastname: Cheng
authors.forename: Linhua
authors.initials: L
authors.lastname: Vatan
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szeliga
authors.forename: Shuang
authors.initials: S
authors.lastname: Wei
authors.forename: Emina
authors.initials: E
authors.lastname: Huang
authors.forename: Emily
authors.initials: E
authors.lastname: Finlayson
authors.forename: Diane
authors.initials: D
authors.lastname: Simeone
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Welling
authors.forename: Alfred
authors.initials: A
authors.lastname: Chang
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.forename: Rebecca
authors.initials: R
authors.lastname: Liu
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D000328:Adult; D000368:Aged; D054357:Chemokine CXCL10 / Q000276:immunology; D054370:Chemokine CXCL9 / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D020381:Interleukin-17 / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology
chemical_list: C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D020381:Interleukin-17; D053583:Interleukin-1beta