Abstract: Objective: To explore the potential pathogenesis of PD-1 inhibitor-induced cutaneous immune-related adverse events (cirAEs) by analyzing differentially expressed miRNAs and conducting bioinformatics studies in the peripheral blood of patients with cirAEs induced by PD-1 inhibitors compared to those without cirAEs. Methods: Peripheral blood samples were collected from three patients with cirAEs and one patient without cirAEs at Southern Medical University, Nanfang Hospital. Transcriptome sequencing was used to analyze the differential miRNA expression profiles between the two groups, and heatmaps and volcano plots were constructed. Target mRNAs were screened using RNAhybrid, miRanda, and TargetScan databases. The common mRNAs identified across the databases were defined as target genes of the respective miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed for the identification and functional enrichment analysis of the target genes. The expression differences of miRNAs were verified using real-time quantitative polymerase chain reaction (RT-qPCR). Results: A comparison between the cirAE group and the control group revealed 72 differentially expressed miRNAs, including 34 upregulated and 38 downregulated miRNAs. The most significantly upregulated miRNAs in cirAE patients were miR-15a-5p (log2FC=7.71, FDR＜0.001) and miR-10a (log2FC=6.67, FDR＜0.001). GO analysis indicates that the significantly differentially expressed miRNA target genes are primarily involved in cellular component and organelle, immune system process, metabolic process, regulation of biological process, signaling, and binding, etc. KEGG pathway analysis reveals significant enrichment of target genes in pathways including PI3K-Akt, VEGF signaling pathways, adherens junction, etc. RT-qPCR results supported the sequencing data. Conclusion: There was a significant alteration in miRNA expression in the peripheral blood of cirAE patients. miR-15a-5p and miR-10a may regulate immune system processes and metabolic processes through the PI3K-Akt signaling pathway, participating in the occurrence of cirAEs.

Key words: cutaneous immune-related adverse events (cirAEs), PD-1 inhibitors, mircoRNA (miRNA), transcriptome sequencing, transcriptomics