A composite score of serum cytokines enables early identification of patients at high risk for irAEs under immune checkpoint inhibition.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced skin cancers. However, potentially severe and irreversible immune-related adverse events (irAEs) represent a major clinical challenge. Identifying reliable predictive biomarkers for irAEs remains critical to balancing efficacy and toxicity. Methods: In this prospective cohort of 131 skin cancer patients receiving ICI we analyzed the expression of 57 cytokines in baseline and longitudinal serum samples and tested their predictive value regarding the occurrence of irAEs. Results: We observed distinct cytokine expression profiles in patients who developed irAEs compared to those who did not, with variations reflecting the affected organ systems, particularly liver and thyroid toxicity. Elevated levels of IL-1RA and CXCL-13 and downregulated levels of IL-7 after the first ICI application significantly correlated with irAEs occurrence. To improve predictive accuracy, we developed a composite cytokine risk score integrating these cytokines, which independently predicted irAE in both univariable and multivariable models. ROC analysis of the cytokine risk score yielded an AUC of 0.710. Time-dependent Cox regression confirmed the cytokine risk score as an independent predictor of irAEs (univariable HR = 1.801 [95%CI=1.424-2.277; p<0.001]; multivariable HR = 1.407 [95%CI=1.072-1.846; p=0.014]). After stratifying patients into low- and high-risk groups, the high-risk patients had a significantly increased hazard of experiencing irAEs. Conclusion: IL-7, IL-1RA, and CXCL-13 represent potential biomarkers for irAEs risk stratification.