Regulatory T cells promote glioma cell stemness through TGF-beta-NF-kappa B-IL6-STAT3 signaling
Open Access
- 11 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 70 (9), 2601-2616
- https://doi.org/10.1007/s00262-021-02872-0
Abstract
Glioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-beta secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-beta acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-kappa B-IL6-STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-beta were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.Funding Information
- National Natural Science Foundation of China (91942314, 81771781, 81802857)
- National Major Science and Technology Projects of China (2020ZX09201- 009)
This publication has 54 references indexed in Scilit:
- A restricted cell population propagates glioblastoma growth after chemotherapyNature, 2012
- Immunity, Inflammation, and CancerCell, 2010
- Autocrine TGF-β Signaling Maintains Tumorigenicity of Glioma-Initiating Cells through Sry-Related HMG-Box FactorsCell Stem Cell, 2009
- Targeting Interleukin 6 Signaling Suppresses Glioma Stem Cell Survival and Tumor GrowthThe International Journal of Cell Cloning, 2009
- TGF-β Increases Glioma-Initiating Cell Self-Renewal through the Induction of LIF in Human GlioblastomaCancer Cell, 2009
- TGFβ in CancerCell, 2008
- Stem Cell Marker CD133 Affects Clinical Outcome in Glioma PatientsClinical Cancer Research, 2008
- High TGFβ-Smad Activity Confers Poor Prognosis in Glioma Patients and Promotes Cell Proliferation Depending on the Methylation of the PDGF-B GeneCancer Cell, 2007
- Interleukin-6 gene amplification and shortened survival in glioblastoma patientsBritish Journal of Cancer, 2007
- Regulatory T cells, tumour immunity and immunotherapyNature Reviews Immunology, 2006