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Published on: August 23, 2024
YTH domain family protein 3 accelerates non-small cell lung cancer immune evasion through targeting CD8+ T
Yisheng Luo1, Chao Zeng2, Zezhong Ouyang1
1Department of Thoracic Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518000, Guangdong Province, China.
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.
Insights
N6-methyladenosine (m6A) reader YTHDF3 promotes non-small cell lung cancer (NSCLC) immune evasion by enhancing PD-L1 stability. YTHDF3 impairs CD8+ T cell activity, offering potential immunotherapy targets for NSCLC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune evasion is a key characteristic of non-small cell lung cancer (NSCLC).
- N6-methyladenosine (m6A) modifications are increasingly recognized for their role in NSCLC immune evasion.
Purpose of the Study:
- To investigate the function and mechanism of the m6A reader YTH domain family protein 3 (YTHDF3) in NSCLC immune evasion.
Main Methods:
- Analysis of YTHDF3 expression in NSCLC tissues.
- Functional assays assessing the impact of YTHDF3 up-regulation and silencing on CD8+ T cell activity and apoptosis.
- Mechanistic studies to identify downstream targets of YTHDF3, including PD-L1 mRNA stability.
Main Results:
- YTHDF3 is highly expressed in NSCLC and serves as an independent prognostic factor.
- YTHDF3 up-regulation suppresses CD8+ T cell antitumor activity and NSCLC cell apoptosis.
- YTHDF3 enhances PD-L1 mRNA transcription stability, promoting immune evasion.
- YTHDF3 targets PD-L1 to facilitate NSCLC immune evasion by reducing CD8+ T cell-mediated killing.
Conclusions:
- YTHDF3 promotes NSCLC immune evasion by targeting PD-L1 and impairing CD8+ T cell antitumor immunity.
- This study provides insights into m6A modification's role in NSCLC antitumor immunity.
- YTHDF3 may represent a novel target for lung cancer immunotherapy.
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