YTH domain family protein 3 accelerates non-small cell lung cancer immune evasion through targeting CD8+ T lymphocytes
Yisheng Luo, Chao Zeng, Zezhong Ouyang, Wenbin Zhu, Jiazhi Wang, Zhiyin Chen, Chunyang Xiao, Guodong Wu, Liang Li, Youhui Qian, Xin Chen, Yu‐Chen Liu, Hao Wu
Abstract
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 N 6 -methyladenosine (m 6 A) on NSCLC immune evasion. Here, this study investigated the function and underlying mechanism of m 6 A 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 m 6 A modification on CD8 + T cell-mediated antitumor immunity in NSCLC, which might inspire an innovation for lung cancer tumor immunotherapy.