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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 improves outcomes in non-small cell lung cancer (NSCLC).
• Resistance to ICB is a significant clinical challenge.
• The role of Protein arginine methyltransferase 5 (PRMT5) in immune checkpoint modulation is not fully understood.

Purpose of the Study:

• To investigate the role of PRMT5 in regulating PD-L1 expression in NSCLC.
• To elucidate the molecular mechanisms underlying PRMT5-mediated PD-L1 regulation.
• To explore the therapeutic potential of combining PRMT5 inhibitors with ICB in NSCLC.

Main Methods:

• Analysis of PRMT family expression and clinical correlations using public databases (Oncomine, TCGA, CPTAC).
• Examination of PRMT5's effect on PD-L1 in LKB1-proficient and LKB1-deficient NSCLC cell lines using inhibitors and shRNA.
• Mechanistic studies including co-immunoprecipitation, cycloheximide chase assays, and mutagenesis.
• Evaluation of T-cell activation in co-culture models.

Main Results:

• Elevated PRMT5 expression in NSCLC correlates with poor survival, reduced T-cell infiltration, and higher PD-L1.
• PRMT5 inhibition downregulates PD-L1 in LKB1-deficient NSCLC but upregulates it in LKB1-proficient NSCLC.
• PRMT5 promotes LKB1 degradation via arginine dimethylation; PRMT5 inhibition stabilizes LKB1, activates AMPK, and induces PD-L1 in LKB1-proficient cells.
• Combination therapy with PRMT5 inhibitor and anti-PD-L1 antibody enhances T-cell activation.

Conclusions:

• A PRMT5-LKB1-AMPK axis controls PD-L1 expression in a context-dependent manner.
• LKB1 status may predict response to combined PRMT5 inhibition and ICB therapy in NSCLC.
• This combination strategy shows promise for overcoming immunotherapy resistance in LKB1-proficient NSCLC.