Heterogeneity of Treg/Th17 According to Cancer Progression and Modification in Biliary Tract Cancers via Self-Producing Cytokines

Mitsuru Kinoshita, Shogo Kobayashi, Kunihito Gotoh, Masahiko Kubo, Koji Hayashi, Yoshifumi Iwagami, Daisaku Yamada, Hirofumi Akita, Takehiro Noda, Tadafumi Asaoka, Yutaka Takeda, Masahiro Tanemura, Hidetoshi Eguchi, Shinya Urakawa, Kumiko Goto, Kayoko Maekawa, Hisashi Wada, Masaki Mori, Yuichiro Doki

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalDigestive Diseases and Sciences
DOIs
Publication statusAccepted/In press - Jan 1 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Gastroenterology

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    Kinoshita, M., Kobayashi, S., Gotoh, K., Kubo, M., Hayashi, K., Iwagami, Y., Yamada, D., Akita, H., Noda, T., Asaoka, T., Takeda, Y., Tanemura, M., Eguchi, H., Urakawa, S., Goto, K., Maekawa, K., Wada, H., Mori, M., & Doki, Y. (Accepted/In press). Heterogeneity of Treg/Th17 According to Cancer Progression and Modification in Biliary Tract Cancers via Self-Producing Cytokines. Digestive Diseases and Sciences. https://doi.org/10.1007/s10620-019-06011-9