2. Academic Validation
  3. Distinct roles of TREM2 in central nervous system cancers and peripheral cancers

Distinct roles of TREM2 in central nervous system cancers and peripheral cancers

  • Cancer Cell. 2024 May 17:S1535-6108(24)00162-4. doi: 10.1016/j.ccell.2024.05.001.
Jian Zhong 1,  Xudong Xing 2,  Yixin Gao 1,  Lei Pei 2,  Chenfei Lu 3,  Huixin Sun 1,  Yanxing Lai 1,  Kang Du 1,  Feizhe Xiao 4,  Ying Yang 5,  Xiuxing Wang 3,  Yu Shi 5,  Fan Bai 6,  Nu Zhang 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong 510080, China.
  • 2 Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China.
  • 3 Department of Cell Biology, National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 4 Department of Scientific Research Section, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 5 Institute of Pathology and Southwest Cancer Centre, Key Laboratory of Tumor Immunopathology of the Ministry of Education of China, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Yu-Yue Pathology Scientific Research Center and Jinfeng Laboratory, Chongqing 400039, China.
  • 6 Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China. Electronic address: [email protected].
  • 7 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong 510080, China. Electronic address: [email protected].
PMID: 38788719 DOI: 10.1016/j.ccell.2024.05.001
Abstract

Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in Cancer Immunotherapy.

Keywords

TREM2; central nervous system cancer; glioblastoma; macrophage; microglia; myeloid cell; tumor microenvironment.

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