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

Zengpanpan Ye; Xiaolin Ai; Kailin Yang; Zhengnan Yang; Fan Fei; Xiaoling Liao; Zhixin Qiu; Ryan C Gimple; Huairui Yuan; Hao Huang; Yanqiu Gong; Chaoxin Xiao; Jing Yue; Liang Huang; Olivier Saulnier; Wei Wang; Peidong Zhang; Lunzhi Dai; Xin Wang; Xiuxing Wang; Young Ha Ahn; Chao You; Jianguo Xu; Xiaoxiao Wan; Michael D Taylor; Linjie Zhao; Jeremy N Rich; Shengtao Zhou

doi:10.1158/2159-8290.CD-22-0455

Journal article

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

Zengpanpan Ye, Xiaolin Ai, Kailin Yang, Zhengnan Yang, Fan Fei, Xiaoling Liao, Zhixin Qiu, Ryan C Gimple, Huairui Yuan, Hao Huang, …

Cancer discovery, Vol.13(4), pp.974-1001

04/03/2023

DOI: 10.1158/2159-8290.CD-22-0455

PMCID: PMC10073346

PMID: 36649564

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10073346/pdf/nihms-1868358.pdfView

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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. 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.

Brain - pathology

Brain Neoplasms - drug therapy

Brain Neoplasms - genetics

Glioblastoma - drug therapy

Glioblastoma - genetics

Humans

Immune Checkpoint Inhibitors - therapeutic use

Macrophages

Microglia

Tumor Microenvironment - physiology

Details

Title: Subtitle: Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma
Creators: Zengpanpan Ye - Sichuan University
Xiaolin Ai - Sichuan University
Kailin Yang - Cleveland Clinic
Zhengnan Yang - Sichuan University
Fan Fei - Fourth People's Hospital of Sichuan Province
Xiaoling Liao - Fourth People's Hospital of Sichuan Province
Zhixin Qiu - UPMC Hillman Cancer Center
Ryan C Gimple - Case Western Reserve University
Huairui Yuan - UPMC Hillman Cancer Center
Hao Huang - Southeast University
Yanqiu Gong - Sichuan University
Chaoxin Xiao - Sichuan University
Jing Yue - Sichuan University
Liang Huang - Sichuan University
Olivier Saulnier - Hospital for Sick Children
Wei Wang - Huzhou Women and Children's Hospital
Peidong Zhang - Sichuan University
Lunzhi Dai - Sichuan University
Xin Wang - Chinese University of Hong Kong
Xiuxing Wang - Nanjing Medical University
Young Ha Ahn - Korea Research Institute of Bioscience and Biotechnology
Chao You - Sichuan University
Jianguo Xu - Sichuan University
Xiaoxiao Wan - Washington University in St. Louis
Michael D Taylor - Hospital for Sick Children
Linjie Zhao - University of Pittsburgh Medical Center
Jeremy N Rich - University of Pittsburgh Medical Center
Shengtao Zhou - Sichuan University
Resource Type: Journal article
Publication Details: Cancer discovery, Vol.13(4), pp.974-1001
DOI: 10.1158/2159-8290.CD-22-0455
PMID: 36649564
PMCID: PMC10073346
NLM abbreviation: Cancer Discov
ISSN: 2159-8274
eISSN: 2159-8290
Grant note: R01 CA268634 / NCI NIH HHS R35 CA197718 / NCI NIH HHS R01 CA238662 / NCI NIH HHS R01 NS103434 / NINDS NIH HHS
Language: English
Date published: 04/03/2023
Academic Unit: Radiation Oncology
Record Identifier: 9984696722802771

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