# Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

## TL;DR

Regulatory T cells boost glioma stem cell traits via a signaling pathway involving TGF-β, IL6, and STAT3, offering new insights into glioma growth and treatment.

## Contribution

The study identifies a novel TGF-β–NF-κB–IL6–STAT3 signaling mechanism by which regulatory T cells promote glioma stemness.

## Key findings

- TGF-β from regulatory T cells enhances glioma stem cell-related gene expression and sphere formation.
- Blocking the IL6 receptor with tocilizumab reduces glioma tumor growth in xenograft models.
- CD133, IL6, and TGF-β expression levels correlate with glioma patient prognosis.

## 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.

The online version of this article (10.1007/s00262-021-02872-0) contains supplementary material, which is available to authorized users.