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IFN-gamma-STAT1-mediated NK2R expression is involved in the induction of antitumor effector CD8(+) T cells in vivo
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Title: | IFN-gamma-STAT1-mediated NK2R expression is involved in the induction of antitumor effector CD8(+) T cells in vivo |
Authors: | Shen, Weidong Browse this author | Wang, Xiangdong Browse this author | Xiang, Huihui Browse this author | Shichi, Shunsuke Browse this author | Nakamoto, Hiroki Browse this author | Kimura, Saori Browse this author | Sugiyama, Ko Browse this author | Taketomi, Akinobu Browse this author | Kitamura, Hidemitsu Browse this author →KAKEN DB |
Keywords: | effector CD8(+) T cells | hepatocellular carcinoma | IFN-gamma | NK2R | STAT1 |
Issue Date: | May-2023 |
Publisher: | John Wiley & Sons |
Journal Title: | Cancer science |
Volume: | 114 |
Issue: | 5 |
Start Page: | 1816 |
End Page: | 1829 |
Publisher DOI: | 10.1111/cas.15738 |
Abstract: | The induction of antitumor effector T cells in the tumor microenvironment is a crucial event for cancer immunotherapy. Neurokinin receptor 2 (NK2R), a G protein-coupled receptor for neurokinin A (NKA), regulates diverse physiological functions. However, the precise role of NKA-NK2R signaling in antitumor immunity is unclear. Here, we found that an IFN-gamma-STAT1 cascade augmented NK2R expression in CD8(+) T cells, and NK2R-mediated NKA signaling was involved in inducing antitumor effector T cells in vivo. The administration of a synthetic analog of double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C), into a liver cancer mouse model induced type I and type II IFNs and significantly suppressed the tumorigenesis of Hepa1-6 liver cancer cells in a STAT1-dependent manner. The reduction in tumor growth was diminished by the depletion of CD8(+) T cells. IFN-gamma stimulation significantly induced NK2R and tachykinin precursor 1 (encodes NKA) gene expression in CD8(+) T cells. NKA stimulation combined with anti-CD3 monoclonal antibody (mAb) treatment significantly augmented IFN-gamma and granzyme B production by CD8(+) T cells compared with the anti-CD3 mAb alone in vitro. ERK1/2 phosphorylation and I kappa B alpha degradation in activated CD8(+) T cells were suppressed under NK2R deficiency. Finally, we confirmed that tumor growth was significantly increased in NK2R-deficient mice compared with that in wild-type mice, and the antitumor effects of poly I:C were abolished by NK2R absence. These findings suggest that IFN-gamma-STAT1-mediated NK2R expression is involved in the induction of antitumor effector T cells in the tumor microenvironment, which contributes to the suppression of cancer cell tumorigenesis in vivo. In this study, we revealed that IFN-gamma-STAT1-mediated NK2R expression is involved in the induction of antitumor effector CD8(+) T cells in the tumor microenvironment, which contributes to suppressing the tumorigenesis of liver cancer cells in vivo. |
Rights: | https://creativecommons.org/licenses/by-nc/4.0/ |
Type: | article |
URI: | http://hdl.handle.net/2115/89264 |
Appears in Collections: | 遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 北村 秀光
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