β2-Microglobulin Maintains Glioblastoma Stem Cells and Induces M2-like Polarization of Tumor-Associated Macrophages,Cancer Research

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β2-Microglobulin Maintains Glioblastoma Stem Cells and Induces M2-like Polarization of Tumor-Associated Macrophages
Cancer Research ( IF 12.5 ) Pub Date : 2022-07-15 , DOI: 10.1158/0008-5472.can-22-0507
Daqi Li _{1,

2} , Qian Zhang _{1,

2} , Lu Li _{1,

2} , Kexin Chen _{1,

2} , Junlei Yang _{1,

2} , Deobrat Dixit ₃ , Ryan C Gimple ₄ , Shusheng Ci _{1,

2} , Chenfei Lu _{1,

2,

5} , Lang Hu _{1,

2,

5} , Jiancheng Gao _{1,

2,

5} , Danyang Shan _{1,

2} , Yangqing Li ₆ , Junxia Zhang ₅ , Zhumei Shi ₅ , Danling Gu ₇ , Wei Yuan ₈ , Qiulian Wu _{3,

9} , Kailin Yang ₁₀ , Linjie Zhao _{3,

9} , Zhixin Qiu _{3,

9,

11} , Deguan Lv ₃ , Wei Gao _{1,

2} , Hui Yang ₁₂ , Fan Lin ₁ , Qianghu Wang ₂ , Jianghong Man ₁₃ , Chaojun Li ₆ , Weiwei Tao ₁₄ , Sameer Agnihotri ₁₅ , Xu Qian _{2,

16} , Yu Shi ₁₇ , Yongping You ₅ , Nu Zhang ₁₈ , Jeremy N Rich _{3,

9,

19} , Xiuxing Wang _{1,

2,

3,

20}

Affiliation

National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, California.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and School of Medicine, Nanjing University, National Resource Center for Mutant Mice, Nanjing, China.
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
Department of Pathology, The Fourth Affiliated Hospital of Nantong University, The First people's Hospital of Yancheng, Yancheng, China.
UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio.
Institute for Translational Brain Research, Fudan University, Shanghai, China.
Department of Neurosurgery, Huashan Hospital, Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, China.
State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.
College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China.
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
Institute of Pathology, Ministry of Education Key Laboratory of Tumor Immunopathology, Southwest Hospital, Chongqing, China.
Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangdong Translational Medicine Innovation Platform, Guangzhou, Guangdong, China.
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

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.

中文翻译：

β2-微球蛋白维持胶质母细胞瘤干细胞并诱导肿瘤相关巨噬细胞的 M2 样极化

胶质母细胞瘤（GBM）是一个复杂的生态系统，包括异质肿瘤群体和肿瘤免疫微环境（TIME），其中主要包含肿瘤相关巨噬细胞（TAM）和小胶质细胞。在这里，我们证明β2-微球蛋白（B2M）是I类主要组织相容性复合体（MHC-I）的一个亚基，促进干细胞样肿瘤群体的维持并将TIME重新编程为抗炎、促肿瘤状态。 B2M 通过与 GBM 干细胞 (GSC) 中的 PIP5K1A 相互作用并促进 MYC 诱导的转化生长因子-β1 (TGFβ1) 分泌来激活 PI3K/AKT/mTOR 信号传导。 B2M 的抑制会减弱 GSC 的存活、自我更新和肿瘤生长。 B2M 诱导的 TGFβ1 分泌激活 TAM 中的旁分泌 SMAD 和 PI3K/AKT 信号传导，并促进 M2 样巨噬细胞表型。这些发现揭示了 B2M 的促肿瘤功能，并表明靶向 B2M 或其下游轴可能为治疗 GBM 提供有效的方法。意义：胶质母细胞瘤细胞中的 β2-微球蛋白信号传导激活 PI3K/AKT/MYC/TGFβ1 轴，维持干细胞并诱导 M2 样巨噬细胞极化，突出了针对胶质母细胞瘤中肿瘤细胞和免疫抑制微环境的潜在治疗策略。

更新日期：2022-07-15

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