1. β2-Microglobulin Maintains Glioblastoma Stem Cells and Induces M2-like Polarization of Tumor-Associated Macrophages
- Author
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Daqi Li, Qian Zhang, Lu Li, Kexin Chen, Junlei Yang, Deobrat Dixit, Ryan C. Gimple, Shusheng Ci, Chenfei Lu, Lang Hu, Jiancheng Gao, Danyang Shan, Yangqing Li, Junxia Zhang, Zhumei Shi, Danling Gu, Wei Yuan, Qiulian Wu, Kailin Yang, Linjie Zhao, Zhixin Qiu, Deguang Lv, Wei Gao, Hui Yang, Fan Lin, Qianghu Wang, Jianghong Man, Chaojun Li, Weiwei Tao, Sameer Agnihotri, Xu Qian, Yu Shi, Yongping You, Nu Zhang, Jeremy N. Rich, and Xiuxing Wang
- Subjects
Cancer Research ,Brain Neoplasms ,Stem Cells ,TOR Serine-Threonine Kinases ,Transforming Growth Factor beta1 ,Phosphatidylinositol 3-Kinases ,Oncology ,Cell Line, Tumor ,Tumor-Associated Macrophages ,Tumor Microenvironment ,Humans ,Glioblastoma ,beta 2-Microglobulin ,Proto-Oncogene Proteins c-akt ,Ecosystem - Abstract
Glioblastoma (GBM) is a complex ecosystem that includes a heterogeneous tumor population and the tumor-immune microenvironment (TIME), prominently containing tumor-associated macrophages (TAM) and microglia. Here, we demonstrated that β2-microglobulin (B2M), a subunit of the class I major histocompatibility complex (MHC-I), promotes the maintenance of stem-like neoplastic populations and reprograms the TIME to an anti-inflammatory, tumor-promoting state. B2M activated PI3K/AKT/mTOR signaling by interacting with PIP5K1A in GBM stem cells (GSC) and promoting MYC-induced secretion of transforming growth factor-β1 (TGFβ1). Inhibition of B2M attenuated GSC survival, self-renewal, and tumor growth. B2M-induced TGFβ1 secretion activated paracrine SMAD and PI3K/AKT signaling in TAMs and promoted an M2-like macrophage phenotype. These findings reveal tumor-promoting functions of B2M and suggest that targeting B2M or its downstream axis may provide an effective approach for treating GBM. Significance: β2-microglobulin signaling in glioblastoma cells activates a PI3K/AKT/MYC/TGFβ1 axis that maintains stem cells and induces M2-like macrophage polarization, highlighting potential therapeutic strategies for targeting tumor cells and the immunosuppressive microenvironment in glioblastoma.
- Published
- 2022