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-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.
Highlights
Glioma is the most common primary brain tumor in humans, characterized by a high invasion rate that results in diffuse tumor infiltration throughout the central nervous system (CNS) [1]
We found that Tregs promoted the proportion of CD133 in U251 cells
CD133 has been accepted as the predominant glioma stem cells (GSCs) marker; other GSC markers include SOX2, NESTIN, and MUSASHI1
Summary
Glioma is the most common primary brain tumor in humans, characterized by a high invasion rate that results in diffuse tumor infiltration throughout the central nervous system (CNS) [1]. Interest has emerged regarding the crosstalk between the cancer stem cell (CSC) niche and other cellular components of the tumor microenvironment (TME), in particular immune cells [8, 9]. Various studies have found that cytokines produced by the infiltrated cells in the TME can have important effects on CSC stemness. Tumor-associated macrophages (TAMs) produced IL6 to promote expansion of CSCs via STAT3 signaling in human hepatocellular carcinoma [10]. Foxp3+IL-17+ T cells promoted development of CSCs in colorectal cancer through the activation of Akt and MAPK pathways [11]. Myeloid-derived suppressor cells (MDSCs) were able to promote stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH crosstalk signaling [12]. IL-22+CD4+ T cells were able to promote colorectal cancer stemness via the STAT3DOT1L pathway [13]. The interactions between CSCs and regulatory T cells (Tregs), which play an important immunosuppressive role in the TME, are still poorly understood
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