Heterogeneity of Treg/Th17 According to Cancer Progression and Modification in Biliary Tract Cancers via Self-Producing
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ORIGINAL ARTICLE
Heterogeneity of Treg/Th17 According to Cancer Progression and Modification in Biliary Tract Cancers via Self‑Producing Cytokines Mitsuru Kinoshita1 · Shogo Kobayashi1 · Kunihito Gotoh1 · Masahiko Kubo1 · Koji Hayashi1 · Yoshifumi Iwagami1 · Daisaku Yamada1 · Hirofumi Akita1 · Takehiro Noda1 · Tadafumi Asaoka1 · Yutaka Takeda1,2 · Masahiro Tanemura1,3 · Hidetoshi Eguchi1 · Shinya Urakawa1,4 · Kumiko Goto4,5 · Kayoko Maekawa4 · Hisashi Wada4 · Masaki Mori1,6 · Yuichiro Doki1 Received: 29 July 2019 / Accepted: 11 December 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract 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. Keywords Biliary tract cancer · Cytokine · Epithelial–mesenchymal transition · T cell differentiation · Interleukin-6 · Transforming growth factor-beta 1
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10620-019-06011-9) contains supplementary material, which is available to authorized users. * Hidetoshi Eguchi [email protected]‑u.ac.jp 1
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2‑2 (E2) Yamadaoka, Suita 537‑8511, Japan
Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan
2
Biliary tract cancer (BTC)
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