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Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma.
Ye, Zengpanpan; Ai, Xiaolin; Yang, Kailin; Yang, Zhengnan; Fei, Fan; Liao, Xiaoling; Qiu, Zhixin; Gimple, Ryan C; Yuan, Huairui; Huang, Hao; Gong, Yanqiu; Xiao, Chaoxin; Yue, Jing; Huang, Liang; Saulnier, Olivier; Wang, Wei; Zhang, Peidong; Dai, Lunzhi; Wang, Xin; Wang, Xiuxing; Ahn, Young Ha; You, Chao; Xu, Jianguo; Wan, Xiaoxiao; Taylor, Michael D; Zhao, Linjie; Rich, Jeremy N; Zhou, Shengtao.
Afiliación
  • Ye Z; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Ai X; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Yang K; Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio.
  • Yang Z; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Fei F; Department of Neurosurgery, Sichuan People's Hospital, Chengdu, Sichuan, P.R. China.
  • Liao X; Department of Neurosurgery, Sichuan People's Hospital, Chengdu, Sichuan, P.R. China.
  • Qiu Z; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, Pennsylvania.
  • Gimple RC; Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
  • Yuan H; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, Pennsylvania.
  • Huang H; School of Biological Science and Medical Engineering, Southeast University, Nanjing, P.R. China.
  • Gong Y; National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, P.R. China.
  • Xiao C; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Yue J; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Huang L; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Saulnier O; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Wang W; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Zhang P; Department of Gynecology, Huzhou Maternity and Child Health Care Hospital, Huzhou, Zhejiang, P.R. China.
  • Dai L; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Wang X; National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, P.R. China.
  • Wang X; Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong, SAR, P.R. China.
  • Ahn YH; School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
  • You C; Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon, Republic of Korea.
  • Xu J; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Wan X; Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu
  • Taylor MD; Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
  • Zhao L; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Rich JN; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Zhou S; Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
Cancer Discov ; 13(4): 974-1001, 2023 04 03.
Article en En | MEDLINE | ID: mdl-36649564
ABSTRACT
Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/-) or CX3CR1+ myeloid cell-specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer.

SIGNIFICANCE:

Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor. This article is highlighted in the In This Issue feature, p. 799.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Glioblastoma Límite: Humans Idioma: En Revista: Cancer Discov Año: 2023 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Glioblastoma Límite: Humans Idioma: En Revista: Cancer Discov Año: 2023 Tipo del documento: Article