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-β secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-β 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-κB–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-β 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.

Background: Glioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and the tumor microenvironment (TME). The aim of this study was to examine how regulatory T cells (Tregs) increase the stemness and tumorigenic potential of glioma cells.Methods: Tumor and peripheral blood samples were collected during surgery from 86 patients with glioma, and 75 samples of adjacent noncancerous tissue were collected, and Regulatory T cells (Tregs) were extracted from blood. Cytological and histochemical analyses were conducted to examine the mechanisms of Treg action on cancer cells. A mouse glioma model was used.Results: Intense infiltration by Tregs facilitated the qualities of GSCs through TGF-β secretion, which helped to coordinate tumor growth. Mechanistic investigations indicated that TGF-b acted on cancer cells to induce expression of the core cancer stem cell-related genes ( CD133, SOX2, NESTIN, MUSASHI1, and ALDH1A ) and to induce sphere formation via the NF-κB–IL6–STAT3 signaling pathway, resulting in increased cancer stemness and tumorigenic potential. Tregs promoted glioma tumor growth, and this effect was abrogated by blockade of the IL6 receptor by tocilizumab, which also demonstrated some therapeutic efficacy in a xenograft model. Expression levels of CD133, IL6 and TGF-β were found to serve as prognostic markers for glioma.Conclusions: Our findings reveal a new immune-associated mechanism underlying Treg-induced GSCs. Efforts to target this network may provide an effective strategy for treating glioma.