Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination.

Autor:	Sun Z; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China.; Department of Radiation Oncology, Air Force Medical Center PLA, Air Force Medical University, Beijing, China., Mai H; Department of Urology, the Third Medical Center of PLA General Hospital, Beijing, China., Xue C; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China., Fan Z; Department of Biotherapy Center, Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, Guangdong, China., Li J; Bioinformatics Center of Academy of Military Medical Sciences, Beijing, China., Chen H; Department of Urology, the Third Medical Center of PLA General Hospital, Beijing, China., Huo N; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China., Kang X; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China., Tang C; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China., Fang L; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China., Zhao H; Department of Oncology, Chinese PLA General Hospital Fifth Medical Center, Beijing, China., Han Y; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China., Sun C; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China., Peng H; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China., Du Y; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China miraclexxj@126.com dunan05@aliyun.com yangjing_301@126.com duyimeng1987@163.com., Yang J; Department of Oncology, Chinese PLA General Hospital Second Medical Center, Beijing, China miraclexxj@126.com dunan05@aliyun.com yangjing_301@126.com duyimeng1987@163.com., Du N; Department of Oncology, Chinese PLA General Hospital Fifth Medical Center, Beijing, China miraclexxj@126.com dunan05@aliyun.com yangjing_301@126.com duyimeng1987@163.com., Xu X; Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China miraclexxj@126.com dunan05@aliyun.com yangjing_301@126.com duyimeng1987@163.com.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Dec 01; Vol. 11 (12). Date of Electronic Publication: 2023 Dec 01.
DOI:	10.1136/jitc-2023-007415
Abstrakt:	Background: Limited response to programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy is a major hindrance of checkpoint immunotherapy in non-small cell lung cancer (NSCLC). The abundance of PD-L1 on the tumor cell surface is crucial for the responsiveness of PD-1/PD-L1 immunotherapy. However, the negative control of PD-L1 expression and the physiological significance of the PD-L1 inhibition in NSCLC immunotherapy remain obscure. Methods: Bioinformatics analysis was performed to profile and investigate the long non-coding RNAs that negatively correlated with PD-L1 expression and positively correlated with CD8+T cell infiltration in NSCLC. Immunofluorescence, in vitro PD-1 binding assay, T cell-induced apoptosis assays and in vivo syngeneic mouse models were used to investigate the functional roles of LINC02418 and mmu-4930573I07Rik in regulating anti-PD-L1 therapeutic efficacy in NSCLC. The molecular mechanism of LINC02418-enhanced PD-L1 downregulation was explored by immunoprecipitation, RNA immunoprecipitation (RIP), and ubiquitination assays. RIP, luciferase reporter, and messenger RNA degradation assays were used to investigate the m6A modification of LINC02418 or mmu-4930573I07Rik expression. Bioinformatics analysis and immunohistochemistry (IHC) verification were performed to determine the significance of LINC02418, PD-L1 expression and CD8+T cell infiltration. Results: LINC02418 is a negative regulator of PD-L1 expression that positively correlated with CD8+T cell infiltration, predicting favorable clinical outcomes for patients with NSCLC. LINC02418 downregulates PD-L1 expression by enhancing PD-L1 ubiquitination mediated by E3 ligase Trim21. Both hsa-LINC02418 and mmu-4930573I07Rik (its homologous RNA in mice) regulate PD-L1 therapeutic efficacy in NSCLC via Trim21, inducing T cell-induced apoptosis in vitro and in vivo . Furthermore, METTL3 inhibition via N6-methyladenosine (m6A) modification mediated by YTHDF2 reader upregulates hsa-LINC02418 and mmu-4930573I07Rik. In patients with NSCLC, LINC02418 expression is inversely correlated with PD-L1 expression and positively correlated with CD8+T infiltration. Conclusion: LINC02418 functions as a negative regulator of PD-L1 expression in NSCLC cells by promoting the degradation of PD-L1 through the ubiquitin-proteasome pathway. The expression of LINC02418 is regulated by METTL3/YTHDF2-mediated m6A modification. This study illuminates the underlying mechanisms of PD-L1 negative regulation and presents a promising target for improving the effectiveness of anti-PD-L1 therapy in NSCLC. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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