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

Objective: LRPPRC 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.

Methods: Expression 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.

Results: LRPPRC 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.

Conclusion: This 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.