Background and Aims: Immune checkpoint inhibitors (ICIs) have significantly improved survival rates for patients with metastatic melanoma. However, these treatments can lead to immune-related adverse events (irAEs), including hepatitis. This exploratory study sought to identify tumour single-nucleotide polymorphisms (SNPs) associated with the risk of ICI-induced hepatitis in melanoma patients. Methods: The study cohort comprised 69 patients with malignant melanoma treated with ICIs at several hospitals in Madrid, Spain. DNA was extracted from formalin-fixed paraffin-embedded tumour biopsies and SNP genotyping was conducted using a MassARRAY platform. Results: Significant associations were found between hepatitis risk and 4 of the 20 SNPs examined. A possible risk effect was shown for the variant GABRP SNP alleles rs11743438 and rs11743735. Among patients homozygous for these variant alleles (v/v), significantly higher proportions developed hepatitis, 75% and 71.4%, respectively, compared to 32.8% and 21.4, respectively, not developing hepatitis (p = 0.046; p = 0.013). However, in the same genotype group comparisons, the RGMA SNP rs4778080 seemed to have a protective effect, as 100% of patients who developed hepatitis were not in the v/v group for this allele (p = 0.043). Additionally, in genotype group comparisons wt/wt versus wt/v + v/v, the PACRG SNP rs55733913 was also associated with a higher risk of ICI-induced hepatitis: 66.7% of patients with hepatitis versus 22.8% without hepatitis in genotype group wt/v + v/v (p = 0.041). Conclusions: This exploratory study identifies candidate tumour SNPs as possible biomarkers to predict the risk of ICI-induced hepatitis, warranting their validation in larger patient cohorts.

Purpose Immune checkpoint inhibitors (ICIs) have revolutionized advanced urothelial carcinoma (UC) treatment, yet efficacy is limited by immune-related adverse events (irAEs) necessitating treatment termination. Identifying biomarkers to predict irAE susceptibility is a critical unmet need for patient management. This exploratory study sought to identify tumor microRNA (miRNA) expression signatures associated with irAE risk in UC patients treated with ICIs. Methods We analyzed a retrospective cohort of 108 UC patients treated with ICI therapy (PD-1 and PD-L1 blockade). Baseline tumor miRNA expression was quantified via RT-qPCR. Statistical analysis was performed to identify associations between baseline miRNA expression levels and the subsequent development of specific irAEs. Results The irAE prevalence was high, affecting approximately one-third of the cohort. Low baseline tumor expression of miR-34c-5p and miR-493-5p was significantly associated with an increased risk of developing pneumonitis (p = 0.037) and asthenia (p = 0.027). Furthermore, borderline associations were observed for miR-146a-5p (hepatitis), miR-222-3p (pneumonitis) and miR-641 (anemia), supporting their roles in regulating immune homeostasis. Conclusion In this exploratory study, tumor miRNA expression profiles, particularly the low baseline expression of miR-34c-5p and miR-493-5p, suggest a possible relationship with higher risk of developing toxicity during ICI treatments. Although further studies are needed to validate the utility of tumor miRNAs expression as biomarkers of ICI-induced toxicity, these preliminary results remark their possible utility as biomarkers in the clinical management of adverse effects from ICI treatment in UC patients.