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调节性 T 细胞通过 TGF-β-NF-κB-IL6-STAT3 信号通路促进神经胶质瘤细胞干性。

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

机构信息

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China.

Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.

出版信息

Cancer Immunol Immunother. 2021 Sep;70(9):2601-2616. doi: 10.1007/s00262-021-02872-0. Epub 2021 Feb 12.

DOI:10.1007/s00262-021-02872-0
PMID:33576874
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8360896/
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.

摘要

神经胶质瘤干细胞（GSCs）有助于神经胶质瘤的恶性生长，但人们对 GSCs 与肿瘤微环境之间的相互作用知之甚少。在这里，我们发现调节性 T 细胞（Tregs）的强烈浸润通过 TGF-β 的分泌促进了 GSCs 的特性，从而有助于肿瘤的协调生长。机制研究表明，TGF-β 通过 NF-κB-IL6-STAT3 信号通路作用于癌细胞，诱导核心癌症干细胞相关基因 CD133、SOX2、NESTIN、MUSASHI1 和 ALDH1A 的表达和球体形成，从而增加癌症干性和肿瘤发生潜力。此外，Tregs 促进了神经胶质瘤肿瘤的生长，而用托珠单抗阻断 IL6 受体可以阻断这种作用，托珠单抗在异种移植模型中也表现出一定的治疗效果。此外，还发现 CD133、IL6 和 TGF-β 的表达水平可作为神经胶质瘤患者的预后标志物。总之，我们的研究结果揭示了 Tregs 诱导的 GSCs 背后的一种新的免疫相关机制。此外，靶向该网络可能是治疗神经胶质瘤的有效策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/a2060aef3f7a/262_2021_2872_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/b4f1b0844f91/262_2021_2872_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/541cd26190af/262_2021_2872_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/b34db2cd6ffc/262_2021_2872_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/06ebf5c149e3/262_2021_2872_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/9d410f1d4e46/262_2021_2872_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/a2060aef3f7a/262_2021_2872_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/b4f1b0844f91/262_2021_2872_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/541cd26190af/262_2021_2872_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/b34db2cd6ffc/262_2021_2872_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/06ebf5c149e3/262_2021_2872_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/9d410f1d4e46/262_2021_2872_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d22f/10991604/a2060aef3f7a/262_2021_2872_Fig6_HTML.jpg

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