Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma-Reference-Cited by-全球学者库

Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma

Published:2023-01-17 Issue:4 Volume:13 Page:974-1001
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Ye Zengpanpan¹^ORCID,Ai Xiaolin¹^ORCID,Yang Kailin²^ORCID,Yang Zhengnan¹^ORCID,Fei Fan³^ORCID,Liao Xiaoling³^ORCID,Qiu Zhixin⁴^ORCID,Gimple Ryan C.⁵^ORCID,Yuan Huairui⁴^ORCID,Huang Hao⁶^ORCID,Gong Yanqiu⁷^ORCID,Xiao Chaoxin¹^ORCID,Yue Jing¹^ORCID,Huang Liang¹^ORCID,Saulnier Olivier⁸⁹^ORCID,Wang Wei¹⁰^ORCID,Zhang Peidong¹^ORCID,Dai Lunzhi⁷^ORCID,Wang Xin¹¹^ORCID,Wang Xiuxing¹²^ORCID,Ahn Young Ha¹³^ORCID,You Chao¹^ORCID,Xu Jianguo¹^ORCID,Wan Xiaoxiao¹⁴^ORCID,Taylor Michael D.⁸⁹¹⁵^ORCID,Zhao Linjie⁴^ORCID,Rich Jeremy N.⁴¹⁶^ORCID,Zhou Shengtao¹^ORCID

Affiliation:

1. 1Department 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.

2. 2Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio.

3. 3Department of Neurosurgery, Sichuan People's Hospital, Chengdu, Sichuan, P.R. China.

4. 4University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, Pennsylvania.

5. 5Department of Pathology, Case Western Reserve University, Cleveland, Ohio.

6. 6School of Biological Science and Medical Engineering, Southeast University, Nanjing, P.R. China.

7. 7National 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.

8. 8Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.

9. 9The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

10. 10Department of Gynecology, Huzhou Maternity and Child Health Care Hospital, Huzhou, Zhejiang, P.R. China.

11. 11Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong, SAR, P.R. China.

12. 12School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.

13. 13Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon, Republic of Korea.

14. 14Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.

15. 15Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.

16. 16Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Abstract

AbstractGlioblastoma (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

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Sichuan Province Science and Technology Support Program

Direct Scientific Research Grants from West China Second Hospital, Sichuan University

Foundation for the National Institutes of Health

Computational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center

Young Investigator Award in Glioblastoma from ASCO Conquer Cancer Foundation

RSNA Research Resident Grant

Publisher

American Association for Cancer Research (AACR)

Subject