ICOSLG-mediated regulatory T-cell expansion and IL-10 production promote progression of glioblastoma

Ryoichi Iwata, Joo Hyoung Lee, Mikio Hayashi, Umberto Dianzani, Kohei Ofune, Masato Maruyama, Souichi Oe, Tomoki Ito, Tetsuo Hashiba, Kunikazu Yoshimura, Masahiro Nonaka, Yosuke Nakano, Lyse Norian, Ichiro Nakano, Akio Asai

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

BACKGROUND: Targeting immune checkpoint proteins has recently gained substantial attention due to the dramatic success of this strategy in clinical trials for some cancers. Inducible T-cell co-stimulator ligand (ICOSLG) is a member of the B7 family of immune regulatory ligands, expression of which in cancer is implicated in disease progression due to regulation of antitumor adaptive immunity. Although aberrant ICOSLG expression has been reported in glioma cells, the underlying mechanisms that promote glioblastoma (GBM) progression remain elusive. METHODS: Here, we investigated a causal role for ICOSLG in GBM progression by analyzing ICOSLG expression in both human glioma tissues and patient-derived GBM sphere cells (GSCs). We further examined its immune modulatory effects and the underlying molecular mechanisms. RESULTS: Bioinformatics analysis and GBM tissue microarray showed that upregulation of ICOSLG expression was associated with poor prognosis in patients with GBM. ICOSLG expression was upregulated preferentially in mesenchymal GSCs but not in proneural GSCs in a tumor necrosis factor-α/nuclear factor-kappaB-dependent manner. Furthermore, ICOSLG expression by mesenchymal GSCs promoted expansion of T cells that produced interleukin-10. Knockdown of the gene encoding ICOSLG markedly reduced GBM tumor growth in immune competent mice, with a concomitant downregulation of interleukin-10 levels in the tumor microenvironment. CONCLUSIONS: Inhibition of the ICOSLG-inducible co-stimulator axis in GBM may provide a promising immunotherapeutic approach for suppressing a subset of GBM with an elevated mesenchymal signature.

Original languageEnglish
Pages (from-to)333-344
Number of pages12
JournalNeuro-oncology
Volume22
Issue number3
DOIs
Publication statusPublished - Mar 5 2020
Externally publishedYes

Keywords

  • ICOSLG
  • glioblastoma
  • glioma stem cell
  • immune escape
  • mesenchymal type

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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  • Cite this

    Iwata, R., Hyoung Lee, J., Hayashi, M., Dianzani, U., Ofune, K., Maruyama, M., Oe, S., Ito, T., Hashiba, T., Yoshimura, K., Nonaka, M., Nakano, Y., Norian, L., Nakano, I., & Asai, A. (2020). ICOSLG-mediated regulatory T-cell expansion and IL-10 production promote progression of glioblastoma. Neuro-oncology, 22(3), 333-344. https://doi.org/10.1093/neuonc/noz204