ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicImmune-Related Biomarkers in Skin and Breast Cancer: Innovations in Immunological Diagnostics and TherapiesView all 9 articles
A composite score of serum cytokines enables early identification of patients at high risk for irAEs under immune checkpoint inhibition
Provisionally accepted
Nina Flatt1Antje Walter1Corinna Kochanek1Maximilian Beikirch1Viola K. DeTemple1Yenny Angela1Imke von Wasielewski2Ralf Gutzmer1
Katrin Schaper-Gerhardt3*- 1Universitätsklinik für Dermatologie, Venerologie, Allergologie und Phlebologie, Johannes Wesling Klinik, Minden, Germany
- 2Medizinische Hochschule Hannover Klinikum Klinik fur Dermatologie Allergologie und Venerologie, Hanover, Germany
- 3Ruhr University Bochum, Universitätsklinik für Dermatologie, Venerologie, Allergologie und Phlebologie, Johannes Wesling Klinik, Minden, Germany
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Background: Immune checkpoint inhibitors (ICIs) 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 occurence. 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.
Keywords: immune checkpoint inhibitors, Immune related adverse events, Cytokines, Skincancer, Melanoma, biomarker
Received: 27 Oct 2025; Accepted: 13 Nov 2025.
Copyright: © 2025 Flatt, Walter, Kochanek, Beikirch, DeTemple, Angela, von Wasielewski, Gutzmer and Schaper-Gerhardt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Katrin Schaper-Gerhardt, katrin.schaper-gerhardt@ruhr-uni-bochum.de
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