ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Tyrosine Protein Kinase SYK-Related Gene Signature in Baseline Immune Cells Associated with Adjuvant Immunotherapy-Induced Immune-Related Adverse Events in Melanoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Omics-based biomarkers of immune-related organ toxicities associated with immune checkpoint inhibitors: a scoping review and evidence map.Frontiers in immunology · 2026Article
- Epigenetics of Malignant Melanoma: Mechanisms, Diagnostic Approaches and Therapeutic Applications.Oncology research · 2026Review
- ChronoimmunoTOX: A Single-Institution Retrospective Study on How the Time of Administration Impacts Immune Checkpoint Inhibitor Efficacy and Toxicity in Melanoma.Journal of clinical medicine · 2025Article
- Gene-expression signature predicts autoimmune toxicity in metastatic melanoma.Journal for immunotherapy of cancer · 2025Article
- Inherited mitochondrial genetics as a predictor of immune checkpoint inhibition efficacy in melanoma.Nature medicine · 2025Article
- Urgent considerations on renal immune-related adverse events in oncology practice.Frontiers in immunology · 2025Review
- Article
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15 authors.
Funding
Abstract
purposeImmune checkpoint inhibition (ICI) shows benefits in adjuvant (AT) and neoadjuvant melanoma treatments. However, ICI frequently induces severe immune-related adverse events (irAE). Unlike metastatic disease, in which irAEs are a clinical trade-off for treatment that improves survival, the toxicity burden from ICI in the AT setting is a substantial clinical problem urging for irAE-predictive biomarkers. EXPERIMENTAL
designWe assessed postsurgical, pre-ICI treatment peripheral CD4+ and CD8+ T cells from clinical trial patients (CheckMate 915) treated with AT nivolumab (n = 130) or ipilimumab/nivolumab (COMBO, n = 82). Performing RNA sequencing differential gene expression analysis, we tested baseline differences associated with severe (grades 3-5) irAEs and constructed an irAE-predictive model using least absolute shrinkage and selection operator-regularized logistic regression.
resultsThe analysis of predicted protein-protein interactions among differentially expressed genes in peripheral CD4+ cells revealed significant enrichment of the spleen tyrosine kinase (SYK) pathway, associated with severe irAEs in COMBO-treated patients. This gene expression signature predicted severe-irAE COMBO patients (χ2P value = 0.001) with 73% accuracy and was independent of disease recurrence (P = 0.79). The irAE-predictive model incorporating this gene expression signature demonstrated 82% accuracy (χ2P value = 8.91E-06).
conclusionsWe identified baseline gene expression differences in key immune pathways of peripheral blood T cells from COMBO-treated patients with grades 3 to 5 irAEs and defined a SYK-related gene signature correctly identifying ∼60% of COMBO-treated patients with grades 3 to 5 irAEs. This finding aligns with our previous work linking anti-CTLA4 irAEs with a germline variant associated with high SYK expression. This gene signature may serve as a baseline biomarker of severe grade 3 to 5 irAE risk, which is especially important in AT treatment.
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