PiRNA-Hsap_1847317 may serve as a novel biomarker of PD-1 inhibitor resistance in patients with advanced non-small cell lung cancer

Abstract Background: Resistance to PD-1 inhibitors poses a major challenge in treating NSCLC. This study explores the epigenetic mechanisms of PD-1 inhibitor resistance, focusing on piRNA expression and related signaling pathways. Methods: High-throughput sequencing was performed on blood samples from three NSCLC patient pairs before and after PD-1 inhibitor resistance to identify differentially expressed piRNAs. The top five were selected for further study. Serum piRNA levels and clinical data from 50 NSCLC patients pre- and post-resistance were analyzed. Target genes of candidate piRNAs were predicted using TargetScan and miRanda, followed by GO and KEGG enrichment analyses. Gene expression was validated via qRT-PCR. Spearman correlation assessed relationships between piRNAs and clinical indicators. ROC curves evaluated predictive value. Results: Five piRNAs (Hsap_2765751, Hsap_249, Hsap_1847317, Hsap_681799, Hsap_857420) were differentially expressed, with Hsap_1847317 significantly upregulated post-resistance (p < 0.001). Target prediction revealed involvement of Hsap_1847317 in the Wnt pathway via AXIN2, NFATC1, PRICKLE4, and CTBP1, with AXIN2 significantly upregulated (p < 0.001). Neutrophil-to-lymphocyte ratio (NLR) also increased post-resistance (p < 0.001) and positively correlated with Hsap_1847317 (r = 0.395, p < 0.05). AUC values were 0.94 for Hsap_1847317 and 0.72 for NLR. Conclusion: Our study showed that Hsap_1847317 and NLR could serve as biomarker for NSCLC immune resistance. These findings contribute to a deeper understanding of the epigenetic regulation of immunotherapy resistance in NSCLC.