Key result
Integrated multi-omics identified pathogenic ISG15+CD8+ T cells in ICI-myocarditis, and an 8-protein random forest panel successfully distinguished active ICI-myocarditis from controls with an AUC of 0.996.
Why the study?
A comprehensive understanding of the cellular and molecular determinants driving immune checkpoint inhibitor-associated myocarditis is essential for improving diagnosis and developing targeted therapies.
Does integrated multi-omics profiling identify distinct pathogenic immune signatures (such as ISG15+CD8+ T cells) and therapeutic targets in ICI-induced myocarditis?
Observational
Does integrated multi-omics profiling identify distinct pathogenic immune signatures (such as ISG15+CD8+ T cells) and therapeutic targets in ICI-induced myocarditis?
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Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The surprising finding came from mouse experiments: tofacitinib, a JAK inhibitor, reduced cardiac inflammation and improved heart function. Yet it did not compromise anti-PD-1 tumor control. In a separate colorectal cancer model, the combination actually improved antitumor activity. The implication is significant: immune toxicity and tumor immunity may be more separable than conventional immunosuppression assumes. Human efficacy and safety remain unproven...”
“A Nature Communications study identified an expanded population of ISG15+ CD8+ T cells in patients with active immunotherapy-related myocarditis. These cells showed inflammatory JAK–STAT signaling and the ability to damage cardiomyocytes in laboratory experiments. The researchers also identified CCL2–CCR2 communication between T cells and monocytes. Blocking CCR2 reduced cardiac inflammation in mice. More unexpectedly, JAK–STAT inhibition improved cardiac function while enhancing anti-PD-1 antitumor responses in mouse models. The implication is significant: suppressing a specific inflammatory program might protect the heart without broadly disabling antitumor immunity.”
The study identifies ISG15+CD8+ T cells as key drivers of cytotoxicity in ICI-myocarditis and highlights the CCL2-CCR2 and JAK-STAT pathways as promising therapeutic targets.
Immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis) is a rare but frequently fatal immune-related adverse event. A comprehensive understanding of the cellular and molecular determinants driving ICI-myocarditis is essential for improving diagnostic precision and developing targeted interventions. We delineate the immune landscape of ICI-myocarditis via scRNA-seq, flow cytometry, Olink proteomics, and multiplex cytokine profiling. We demonstrate that high levels of baseline ISG15⁺CD8⁺ T cells are linked to the proinflammatory features of monocytes and in vitro experiments confirm the existence of circulating ISG15⁺CD8⁺ T cells with a high potential to induce cardiomyocyte apoptosis, supporting their pathogenic potential for cardiomyocyte cytotoxicity. Notably, intercellular crosstalk between these subsets is possibly mediated via the CCL2-CCR2 axis, and its blockade attenuated ICI-induced cardiac injury in vivo. Based on the inflammatory signature in ICI-myocarditis, we develop an 8-protein custom panel with promising performance in distinguishing ICI-myocarditis from other ICIs-treated controls. JAK-STAT pathway activation promotes inflammatory programs in both ISG15⁺CD8⁺ T cells and monocytes. Furthermore, JAK-STAT inhibition ameliorates cardiac dysfunction and inflammatory infiltration while enhancing the response to anti-PD-1 therapy in mouse models. In summary, this study implicates immune-pathogenic features of ICI-myocarditis and provides a possible basis for future therapies.
Zhang et al. (2026) conducted an observational in Immune checkpoint inhibitor-associated myocarditis. Active ICI-myocarditis (act-ICIAM) status vs. ICI-treated controls without myocarditis (no-ICIAM) was evaluated on Diagnostic performance (AUC) of an 8-protein Random Forest machine learning model in distinguishing active ICI-myocarditis from ICI-treated controls (AUC 0.996, 95% CI 0.99-1.00). Integrated multi-omics identified pathogenic ISG15+CD8+ T cells in ICI-myocarditis, and an 8-protein random forest panel successfully distinguished active ICI-myocarditis from controls with an AUC of 0.996.
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