Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments.
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.
Kryczek
Ilona
I
Department of Surgery, University of Michigan, Ann Arbor, MI 48109-0669, USA. ilonak@med.umich.edu
Banerjee
Mousumi
M
Cheng
Pui
P
Vatan
Linhua
L
Szeliga
Wojciech
W
Wei
Shuang
S
Huang
Emina
E
Finlayson
Emily
E
Simeone
Diane
D
Welling
Theodore H
TH
Chang
Alfred
A
Coukos
George
G
Liu
Rebecca
R
Zou
Weiping
W
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
C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D020381:Interleukin-17; D053583:Interleukin-1beta