Identification of plasma exosomal miRNAs as predictive biomarkers for therapeutic efficacy of programmed cell death 1 (PD-1) blockade plus chemotherapy in gastric cancer patients

Methods

Serum exosomes were extracted from 11 GC patients (5 in primary cohort and 6 in the validation cohort) treated with SOX and camrelizumab (a PD-1 inhibitor). High-throughput sequencing identified miRNA expression profiles, followed by hierarchical clustering and differential expression analysis. Functional enrichment analysis of target genes for significantly upregulated miRNAs was performed using Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases.

Validation of candidate miRNAs was carried out using quantitative polymerase chain reaction (qPCR) in an independent cohort. Results: MiRNA sequencing identified 3083 miRNAs, with 74 differentially expressed between responders and non-responders (42 upregulated and 32 downregulated). GO and KEGG pathway analysis of the top 20 upregulated miRNAs indicated significant involvement of target genes in transcription regulation, cytoplasmic processes, and protein binding, with key pathways including PI3K-AKT, MAPK, RAP1, and RAS signaling.

QPCR validation demonstrated significant differences in the expression levels of miRNA451a and miRNA142-5p between responders and non-responders, consistent with sequencing findings. Conclusion: Our study identifies specific plasma exosomal miRNAs that differentiate between responders and non-responders to PD-1 monoclonal antibody therapy combined with chemotherapy in GC patients. These miRNAs hold potential as predictive biomarkers, paving the way for precision medicine and personalized therapy in GC treatment.