机构：[1]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, P. R. China四川大学华西医院[2]Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA[3]Department of Neurosurgery, Sichuan People's Hospital, Chengdu, Sichuan, P. R. China[4]University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA[5]Department of Pathology, Case Western Reserve University, Cleveland, OH, USA[6]School of Biological Science and Medical Engineering, Southeast University, Nanjing, P. R. China[7]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四川大学华西医院[8]Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada[9]The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada[10]Department of Gynecology, Huzhou Maternity & Child Health Care Hospital, Huzhou, Zhejiang, P. R. China[11]Department of Surgery, The Chinese University of Hong Kong. Prince of Wales Hospital,Shatin, N.T., Hong Kong, SAR, P. R. China[12]School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, P.R. China[13]Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea[14]Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA[15]Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, M5S 3E1, Canada[16]Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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 microglia-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. Pharmacological NR4A2 inhibition attenuated the pro-tumorigenic TIME, and targeting the NR4A2 or SQLE enhanced 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.
基金：
National Natural Science Foundation of China (grant #82273255,
#81822034, #81821002, and #81773119 to S.Z, grant #82103127 to Z.Y., grant #82202889 to
X.A.), National Key Research and Development Program of China (grant #2022YFA1106600,
#2017YFA0106800 and #2018YFA0109200 to S.Z), Sichuan Science-Technology Project (grant
#22ZYZYTS0070 and #2019YFH0144 to S.Z), Direct Scientific Research Grants from West China Second Hospital, Sichuan University (grant #KS021 and #K1907 to S.Z), NIH grants
(CA197718, NS103434, CA268634, and CA238662 to J.N.R), Computational Genomic
Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center (grant
#T32CA094186 to K.Y), Young Investigator Award in Glioblastoma from ASCO Conquer
Cancer Foundation (to K.Y), and RSNA Research Resident Grant (to K.Y.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类|1 区医学
小类|1 区肿瘤学
最新[2023]版：
大类|1 区医学
小类|1 区肿瘤学
第一作者：
第一作者机构：[1]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, P. R. China
共同第一作者：
通讯作者：
通讯机构：[1]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, P. R. China[4]University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA[16]Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA[*1]University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA[*2]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, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
推荐引用方式(GB/T 7714)：
Zengpanpan Ye,Xiaolin Ai,Kailin Yang,et al.Targeting Microglial Metabolic Rewiring Synergizes with Immune Checkpoint Blockade Therapy for Glioblastoma[J].Cancer discovery.2023,doi:10.1158/2159-8290.CD-22-0455.
APA：
Zengpanpan Ye,Xiaolin Ai,Kailin Yang,Zhengnan Yang,Fan Fei...&Shengtao Zhou.(2023).Targeting Microglial Metabolic Rewiring Synergizes with Immune Checkpoint Blockade Therapy for Glioblastoma.Cancer discovery,,
MLA：
Zengpanpan Ye,et al."Targeting Microglial Metabolic Rewiring Synergizes with Immune Checkpoint Blockade Therapy for Glioblastoma".Cancer discovery .(2023)
医学