PRMT5-mediated methylation of LKB1 controls PD-L1 expression in NSCLC.

BACKGROUND

Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has significantly improved outcomes in non-small cell lung cancer (NSCLC), yet resistance remains a major clinical challenge. Protein arginine methyltransferase 5 (PRMT5) is an oncogenic regulator associated with poor prognosis, but its role in immune checkpoint modulation and underlying molecular mechanisms remain incompletely defined.

MATERIALS AND

METHODS

PRMT family expression and clinical correlations were analyzed using Oncomine, TCGA, and CPTAC databases. The effect of PRMT5 on PD-L1 was examined in LKB1-proficient and LKB1-deficient NSCLC cell lines using pharmacological inhibitors (GSK3326595, JNJ-64619178) and shRNA knockdown. Mechanistic analyses included co-immunoprecipitation (Co-IP), cycloheximide chase assays, and site-directed mutagenesis of LKB1 arginine residues. T-cell activation was evaluated using co-culture models.

RESULTS

Elevated PRMT5 expression in NSCLC was associated with poor survival, reduced CD4+/CD8+ T-cell infiltration, and higher PD-L1 expression in clinical datasets. Functional analyses revealed context-dependent regulation of PD-L1 by PRMT5. PRMT5 inhibition reduced or failed to induce PD-L1 in LKB1-deficient cells but upregulated PD-L1 in LKB1-proficient cells. Mechanistically, PRMT5 interacted with LKB1 and promoted its degradation through symmetric arginine dimethylation at R409. Conversely, PRMT5 inhibition stabilized LKB1, activated AMPK signaling, and induced PD-L1 expression in LKB1-proficient cells. Combination treatment with a PRMT5 inhibitor and anti-PD-L1 antibody further enhanced T-cell activation in co-culture models.

CONCLUSION

These findings identify a PRMT5-LKB1-AMPK regulatory axis controlling PD-L1 expression in a cell-context-dependent manner and suggest that LKB1 status may serve as a predictive biomarker for combining PRMT5 inhibitors with ICB in NSCLC. This strategy offers a potential therapeutic avenue to overcome immunotherapy resistance in LKB1-proficient NSCLC.