2. Academic Validation
  3. Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands

Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands

  • Nat Commun. 2022 Aug 15;13(1):4795. doi: 10.1038/s41467-022-32311-2.
Jian Zhong  # 1 2 3,  Xuesong Yang  # 1 2 3,  Junju Chen  # 1 2 3,  Kejun He  # 1 2 3,  Xinya Gao 1 2 3,  Xujia Wu 1 2 3,  Maolei Zhang 1 2 3,  Huangkai Zhou 1 2 3,  Feizhe Xiao 4,  Lele An 5 6,  Xiuxing Wang 7 8 9 10,  Yu Shi 11 12,  Nu Zhang 13 14 15
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 2 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, 510080, China.
  • 3 Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, 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, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 6 Key Laboratory of Tumour Immunopathology of the Ministry of Education of China, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 7 National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. drxiuxingwang@163.com.
  • 8 Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. drxiuxingwang@163.com.
  • 9 Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. drxiuxingwang@163.com.
  • 10 Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. drxiuxingwang@163.com.
  • 11 Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. drshiyu@126.com.
  • 12 Key Laboratory of Tumour Immunopathology of the Ministry of Education of China, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. drshiyu@126.com.
  • 13 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. zhangnu2@mail.sysu.edu.cn.
  • 14 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, 510080, China. zhangnu2@mail.sysu.edu.cn.
  • 15 Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. zhangnu2@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 35970825 DOI: 10.1038/s41467-022-32311-2
Abstract

Glioblastoma (GBM) is a highly aggressive primary brain tumour and is resistant to nearly all available treatments, including natural killer (NK) cell immunotherapy. However, the factors mediating NK cell evasion in GBM remain largely unclear. Here, we report that EZH2-92aa, a protein encoded by circular EZH2, is overexpressed in GBM and induces the immune evasion of GBM stem cells (GSCs) from NK cells. Positively regulated by DEAD-box helicase 3 (DDX3), EZH2-92aa directly binds the major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) promoters and represses their transcription; it also indirectly represses UL16-binding protein (ULBP) transcription by stabilizing EZH2. The downregulation of NK group 2D ligands (NKG2DLs, including MICA/B and ULBPs) in GSCs mediates NK cell resistance. Moreover, stable EZH2-92aa knockdown enhances NK cell-mediated GSC eradication in vitro and in vivo and synergizes with anti-PD1 therapy. Our results highlight the immunosuppressive function of EZH2-92aa in inhibiting the NK cell response in GBM and the clinical potential of targeting EZH2-92aa for NK-cell-directed immune therapy.

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