Ryoichi Iwata1, Joo Hyoung Lee2, Mikio Hayashi3, Umberto Dianzani4, Kohei Ofune1, Masato Maruyama5, Souichi Oe6, Tomoki Ito7, Tetsuo Hashiba1, Kunikazu Yoshimura1, Masahiro Nonaka1, Yosuke Nakano5, Lyse Norian8, Ichiro Nakano9, Akio Asai1. 1. Department of Neurosurgery, Kansai Medical University, Hirakata, Japan. 2. Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA. 3. Department of Physiology, Kansai Medical University, Hirakata, Japan. 4. Interdisciplinary Research Center of Autoimmune Diseases, Department of Health Sciences, "A. Avogadro" University of Eastern Piedmont, Novara, Italy. 5. Department of Anatomy and Brain Science, Kansai Medical University, Hirakata, Japan. 6. Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan. 7. First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan. 8. Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA. 9. Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
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.
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 humanglioma 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 GBMtumor 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.
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