TY - JOUR
T1 - Heterogeneity of Treg/Th17 According to Cancer Progression and Modification in Biliary Tract Cancers via Self-Producing Cytokines
AU - Kinoshita, Mitsuru
AU - Kobayashi, Shogo
AU - Gotoh, Kunihito
AU - Kubo, Masahiko
AU - Hayashi, Koji
AU - Iwagami, Yoshifumi
AU - Yamada, Daisaku
AU - Akita, Hirofumi
AU - Noda, Takehiro
AU - Asaoka, Tadafumi
AU - Takeda, Yutaka
AU - Tanemura, Masahiro
AU - Eguchi, Hidetoshi
AU - Urakawa, Shinya
AU - Goto, Kumiko
AU - Maekawa, Kayoko
AU - Wada, Hisashi
AU - Mori, Masaki
AU - Doki, Yuichiro
N1 - Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85077059291&partnerID=8YFLogxK
U2 - 10.1007/s10620-019-06011-9
DO - 10.1007/s10620-019-06011-9
M3 - Article
C2 - 31853779
AN - SCOPUS:85077059291
SN - 0163-2116
VL - 65
SP - 2937
EP - 2948
JO - Digestive Diseases and Sciences
JF - Digestive Diseases and Sciences
IS - 10
ER -
