2. Academic Validation
  3. YTH domain family protein 3 accelerates non-small cell lung cancer immune evasion through targeting CD8+ T lymphocytes

YTH domain family protein 3 accelerates non-small cell lung cancer immune evasion through targeting CD8+ T lymphocytes

  • Cell Death Discov. 2024 Jul 11;10(1):320. doi: 10.1038/s41420-024-02084-2.
Yisheng Luo # 1,  Chao Zeng # 2,  Zezhong Ouyang # 1,  Wenbin Zhu 1,  Jiazhi Wang 1,  Zhiyin Chen 1,  Chunyang Xiao 1,  Guodong Wu 1,  Liang Li 1,  Youhui Qian 1,  Xin Chen 3,  Yuchen Liu 4,  Hao Wu 5
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518000, Guangdong Province, China.
  • 2 Department of Respiratory and Critical Care Medicine, Peking University Shenzhen Hospital, Shenzhen, 518000, Guangdong Province, China.
  • 3 National Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, Guangdong Province, China.
  • 4 Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518000, Guangdong Province, China. liuyuchen_szu@yeah.net.
  • 5 Department of Thoracic Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518000, Guangdong Province, China. wuhaoszu@yeah.net.
  • # Contributed equally.
PMID: 38992016 DOI: 10.1038/s41420-024-02084-2
Abstract

Immune evasion is one of the critical hallmarks of malignant tumors, especially non-small cell lung Cancer (NSCLC). Emerging findings have illustrated the roles of N6-methyladenosine (m6A) on NSCLC immune evasion. Here, this study investigated the function and underlying mechanism of m6A reader YTH domain family protein 3 (YTHDF3) on NSCLC immune evasion. YTHDF3 was found to be highly expressed in NSCLC tissue and act as an independent prognostic factor for overall survival. Functionally, up-regulation of YTHDF3 impaired the CD8+ T antitumor activity to deteriorate NSCLC immune evasion, while YTHDF3 silencing recovered the CD8+ T antitumor activity to inhibit immune evasion. Besides, YTHDF3 up-regulation reduced the Apoptosis of NSCLC cells. Mechanistically, PD-L1 acted as the downstream target for YTHDF3, and YTHDF3 could upregulate the transcription stability of PD-L1 mRNA. Overall, YTHDF3 targeted PD-L1 to promote NSCLC immune evasion partially through escaping effector cell cytotoxicity CD8+ T mediated killing and antitumor immunity. In summary, this study provides an essential insight for m6A modification on CD8+ T cell-mediated antitumor immunity in NSCLC, which might inspire an innovation for lung Cancer tumor immunotherapy.

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