2. Academic Validation
  3. ALKBH5 promotes PD-L1-mediated immune escape through m6A modification of ZDHHC3 in glioma

ALKBH5 promotes PD-L1-mediated immune escape through m6A modification of ZDHHC3 in glioma

  • Cell Death Discov. 2022 Dec 24;8(1):497. doi: 10.1038/s41420-022-01286-w.
Wenhui Tang # 1,  Ningbo Xu # 2,  Jian Zhou 1,  Zhenyan He 3,  Cameron Lenahan 4,  Chenyang Wang 1,  Huangyi Ji 5,  Boyang Liu 1,  Yujiao Zou 6,  Huijun Zeng 1,  Hongbo Guo 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
  • 2 Department of Interventional Therapy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
  • 3 Department of Neurosurgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, 450003, China.
  • 4 Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, 88003, NM, USA.
  • 5 Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
  • 6 Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
  • 7 Department of Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. guohongbo911@126.com.
  • # Contributed equally.
PMID: 36566230 DOI: 10.1038/s41420-022-01286-w
Abstract

N6-methylation of adenosine (m6A) is one of the most frequent chemical modifications in eukaryotic RNAs and plays a vital role in tumorigenesis and progression. Recently, emerging studies have shown that m6A modification by ALKBH5 was associated with immunotherapy response in various types of Cancer. However, whether m6A demethylases ALKBH5 participate in regulating the tumor immune microenvironment and the efficacy of immunotherapy in glioblastoma remain unknown. Here, we found that deletion of ALKBH5 significantly inhibited the growth of glioma allografts, rescued the antitumoral immune response, and increased cytotoxic lymphocyte infiltration and proinflammatory cytokines in CSF while significantly suppressing PD-L1 protein expression. m6A-methylated RNA immunoprecipitation Sequencing and RNA Sequencing identify ZDDHC3 as the direct target of ALKBH5. Mechanically, ALKBH5 deficiency impairs the YTHDF2-mediated stability of ZDHHC3 mRNA, thereby suppressing PD-L1 expression by accelerating PD-L1 degradation in glioma. In addition, genetic deletion or pharmacological inhibition of ALKBH5 with IOX1 enhances the therapeutic efficacy of anti-PD-1 treatment in preclinical mice models. These data suggest that the combination of anti-PD-1 therapy and ALKBH5 inhibition may be a promising treatment strategy in glioma.

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