FKBP5 regulation on anti-PD-1 therapy
Yamaguchi, Izumi Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Nakajima, Kohei Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Shono, Kenji Tokushima University
Fujihara, Toshitaka Tokushima University Tokushima University Educator and Researcher Directory
Shikata, Eiji Tokushima University
Yamaguchi, Tadashi Tokushima University
Kitazato, Keiko Tokushima University
Sampetrean, Oltea Keio University
Saya, Hideyuki Keio University
Takagi, Yasushi Tokushima University Tokushima University Educator and Researcher Directory
Thesis or Dissertation
Background. Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1.
Methods. Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro.
Results. Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5).
Conclusions. Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects.
Oxford University Press|the Society for Neuro-Oncology|the European Association of Neuro-Oncology
本論文は, 著者Izumi Yamaguchiの学位論文として提出され, 学位審査・授与の対象となっている。
© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
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Doctor of Medical Science