Data from Tyrosine Protein Kinase SYK-Related Gene Signature in Baseline Immune Cells Associated with Adjuvant Immunotherapy–Induced Immune-Related Adverse Events in Melanoma

AbstractPurpose: Immune 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 Design: We 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. Results: The 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). Conclusions: We 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.