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

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 anti-tumor 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-/NF-ĸB-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-ICOS axis in GBM may provide a promising immunotherapeutic approach for suppressing a subset of GBM with an elevated mesenchymal signature.

Plasma IL-8 and ICOSLG as prognostic biomarkers in glioblastoma

“…Plasma soluble ICOSLG was the only checkpoint molecule associated with OS in multivariate analysis. A recent study found that ICOSLG was expressed and secreted by mesenchymal GBM cells 36 and absent in normal brain, 36 , 37 and this is similar to our findings. Iwata et al suggest that soluble ICOSLG released from mesenchymal GBM cells induces CD4+ICOS+Foxp3+T cells (regulatory T cells), IL-10 production and suppression of general T cell proliferation.…”

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

“…Additionally, the predictive values of immune cells have been extensively investigated. It was demonstrated that high levels of M2-type macrophages (marked as CD204 or CD206) (Ding et al, 2014), neutrophils (Liang et al, 2014), Tregs (Iwata et al, 2019) were defined as the adverse prognostic factors in glioma. Conversely, high levels of M1-type macrophages (Ding et al, 2014), CD8 + T cells (Kmiecik et al, 2013) were identified as protective factors in glioma.…”

Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

“…[35] Iwata et al reported that TNF-treatment of PN GSCs dramatically increased NF-B activity, while silencing of NF-B attenuated ICOSLG expression (typically associated with MES) after TNF-treatment. [48] Another interesting work relates to the involvement of serine/threonine kinase MLK4 in TNF-mediated NF-B activation and mesenchymal transformation. [49] Two other review articles cover the other aspects of the NF-B role in mesenchymal transformation and we will not further discuss here.…”