LRPPRC facilitates tumor progression and immune evasion through upregulation of m6A modification of PD-L1 mRNA in hepatocellular carcinoma

Frontiers in Immunology

Immunology

Yayun Cui¹  Heng Li²  Amao Tang³  Houhong Wang⁴  Huihui Gong⁵ 

[1] Department of Cancer Radiotherapy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (Anhui Provincial Cancer Hospital), Hefei, Anhui, China;Department of Comprehensive Surgery, Anhui Provincial Cancer Hospital, West District of The First Affiliated Hospital of USTC, Hefei, Anhui, China;Department of Gastroenterology, The Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China;Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China;Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom;

关键词: hepatocellular carcinoma;    LRPPRC;    PD-L1;    immune evasion;    m6A modification;    anti-tumor immunity;    tumor progression;   

DOI  :  10.3389/fimmu.2023.1144774

 received in 2023-01-15, accepted in 2023-03-07,  发布年份 2023

来源: Frontiers

【 摘 要 】

ObjectiveLRPPRC is a newly discovered N6-methyladenosine (m6A) modification reader, which potentially affects hepatocellular carcinoma (HCC) progression. PD-L1 in tumor cells is essential for tumor immune evasion. This work investigated the LRPPRC-mediated m6A-modification effect on PD-L1 mRNA and immune escape in HCC.MethodsExpression and clinical implication of LRPPRC and PD-L1 were measured in human HCC cohorts. The influence of LRPPRC on malignant behaviors of HCC cells was investigated through in vitro assays and xenograft tumor murine models. The posttranscriptional mechanism of LRPPRC on PD-L1 and anti-tumor immunity was elucidated in HCC cells via RIP, MeRIP−qPCR, RNA stability, immunohistochemical staining, and so forth.ResultsLRPPRC exhibited the notable upregulated in human HCC tissues, which was in relation to advanced stage and worse overall survival and disease-free survival. Impaired proliferative capacity and G2/M phage arrest were found in LRPPRC-knockout cells, with increased apoptotic level, and attenuated migratory and invasive abilities. In HCC patients and murine models, LRPPRC presented a positive interaction with PD-L1, with negative associations with CD8+, and CD4+ T-cell infiltrations and chemokines CXCL9, and CXCL10. LRPPRC loss downregulated the expression of PD-L1 and its m6A level in HCC cells. Moreover, LRPPRC suppression mitigated tumor growth in murine models and improved anti-tumor immunity and immune infiltration in tumors.ConclusionThis work unveiled that LRPPRC may posttranscriptionally upregulate PD-L1 partially with an m6A-dependent manner for heightening mRNA stabilization of PD-L1 and provided a new mechanism for m6A regulator-mediated immunosuppression in HCC.

【 授权许可】

Unknown   
Copyright © 2023 Wang, Tang, Cui, Gong and Li