Heterogeneity of Treg/Th17 According to Cancer Progression and Modification in Biliary Tract Cancers via Self-Producing Cytokines.
Aged
Antimetabolites, Antineoplastic
/ therapeutic use
Biliary Tract Neoplasms
/ drug therapy
Cell Differentiation
Cells, Cultured
Coculture Techniques
Cytokines
/ metabolism
Deoxycytidine
/ analogs & derivatives
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition
Female
Forkhead Transcription Factors
/ metabolism
Humans
Interleukin-17
/ metabolism
Interleukin-6
/ metabolism
Lymphocytes, Tumor-Infiltrating
/ drug effects
Male
Middle Aged
Phenotype
Retrospective Studies
T-Lymphocytes, Regulatory
/ drug effects
Th17 Cells
/ drug effects
Transforming Growth Factor beta1
/ metabolism
Tumor Microenvironment
Gemcitabine
Biliary tract cancer
Cytokine
Epithelial–mesenchymal transition
Interleukin-6
T cell differentiation
Transforming growth factor-beta 1
Journal
Digestive diseases and sciences
ISSN: 1573-2568
Titre abrégé: Dig Dis Sci
Pays: United States
ID NLM: 7902782
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
29
07
2019
accepted:
11
12
2019
pubmed:
20
12
2019
medline:
1
1
2021
entrez:
20
12
2019
Statut:
ppublish
Résumé
We previously demonstrated that inflammatory cytokine interleukin-6 (IL-6) was produced during cancer progression, worked together with transforming growth factor-beta 1 (TGF-β1), and induced the epithelial-mesenchymal transition (EMT) with chemo-resistance against gemcitabine (GR) at the invasion front of biliary tract cancers (BTCs). However, the significance of cytokine-induced T cell accumulation at the tumor microenvironment in biliary tract cancer (BTC) is not well understood. Because these cytokines (IL-6 and TGF-β1) are able to differentiate naïve T cells into Foxp3-expressing T cells (Tregs) and/or IL-17-producing T helper 17 (Th17) cells, we investigated the relationship between heterogeneous, cancer-producing cytokines and T cell differentiation. In total, 127 curative resected specimens from patients with BTCs at Osaka University Hospital between 2000 and 2012 were evaluated for IL-6, TGF-β1, Tregs, and Th17 cells by immunohistochemistry. The ability of BTC-GR cells to undergo T cell differentiation was investigated in vitro. Tregs accumulated at the tumor center and Th17 cells accumulated at the invasion front during cancer progression and/or metastasis; each signaled poor prognosis. Treg accumulation was related to TGF-β1 expression by cancer cells, and Th17 cell accumulation was related to IL-6 expression by cancer cells, in resected specimens; this was confirmed in vitro. Compared with parent cells, GR cells produced IL-6 but not TGF-β1 in a time-dependent manner, had EMT features, and induced T cell differentiation to Th17 cells but not Tregs. Cytokines produced by cancer cells (IL-6 and TGF-β1) induced heterogeneity of Tregs and Th17 cells in the tumor microenvironment, supporting progression of BTC.
Sections du résumé
BACKGROUND/AIM
We previously demonstrated that inflammatory cytokine interleukin-6 (IL-6) was produced during cancer progression, worked together with transforming growth factor-beta 1 (TGF-β1), and induced the epithelial-mesenchymal transition (EMT) with chemo-resistance against gemcitabine (GR) at the invasion front of biliary tract cancers (BTCs). However, the significance of cytokine-induced T cell accumulation at the tumor microenvironment in biliary tract cancer (BTC) is not well understood. Because these cytokines (IL-6 and TGF-β1) are able to differentiate naïve T cells into Foxp3-expressing T cells (Tregs) and/or IL-17-producing T helper 17 (Th17) cells, we investigated the relationship between heterogeneous, cancer-producing cytokines and T cell differentiation.
METHODS
In total, 127 curative resected specimens from patients with BTCs at Osaka University Hospital between 2000 and 2012 were evaluated for IL-6, TGF-β1, Tregs, and Th17 cells by immunohistochemistry. The ability of BTC-GR cells to undergo T cell differentiation was investigated in vitro.
RESULTS
Tregs accumulated at the tumor center and Th17 cells accumulated at the invasion front during cancer progression and/or metastasis; each signaled poor prognosis. Treg accumulation was related to TGF-β1 expression by cancer cells, and Th17 cell accumulation was related to IL-6 expression by cancer cells, in resected specimens; this was confirmed in vitro. Compared with parent cells, GR cells produced IL-6 but not TGF-β1 in a time-dependent manner, had EMT features, and induced T cell differentiation to Th17 cells but not Tregs.
CONCLUSION
Cytokines produced by cancer cells (IL-6 and TGF-β1) induced heterogeneity of Tregs and Th17 cells in the tumor microenvironment, supporting progression of BTC.
Identifiants
pubmed: 31853779
doi: 10.1007/s10620-019-06011-9
pii: 10.1007/s10620-019-06011-9
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Cytokines
0
FOXP3 protein, human
0
Forkhead Transcription Factors
0
IL6 protein, human
0
Interleukin-17
0
Interleukin-6
0
TGFB1 protein, human
0
Transforming Growth Factor beta1
0
Deoxycytidine
0W860991D6
Gemcitabine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM