Work

977 An ICOS–IFN-γ T-cell signature links CNS immune-related adverse events and immune-mediated hepatitis following dual CTLA-4/PD-1 blockade

Year: 2026

Type: conference-abstract

Abstract: Background Combined CTLA-4 and PD-1 checkpoint inhibition has improved outcomes for metastatic melanoma but can induce severe immune-related adverse events (irAEs), including inflammatory toxicities affecting the central nervous system (CNS). 1 2 The immunological mechanisms underlying CNS irAEs remain poorly understood. We aimed to characterize the immune landscape associated with CNS irAEs and identify potential pathogenic mechanisms.Methods Patients with metastatic melanoma treated with combined CTLA-4 and PD-1 blockade (n = 240) were evaluated for CNS irAEs and associated toxicities. Peripheral blood samples were collected from patients with CNS irAEs, other irAEs, and toxicity-free controls. Immune profiling was performed using flow cytometry, Olink inflammation proteomics, and longitudinal single-cell RNA sequencing. Cerebrospinal fluid (CSF) from patients with CNS irAEs was analyzed and compared with samples from viral encephalitis and systemic lupus erythematosus controls.Results Twelve of 240 patients developed CNS irAEs, of whom 9 (75%) had concurrent immune-mediated hepatitis. Patients with CNS irAEs exhibited a distinct immune phenotype characterized by increased frequencies of ICOS-expressing CD4 + and CD8+ T cells together with elevated IFN-γ and the IFN-γ-associated chemokines CXCL9, CXCL10, and CXCL11. A similar immune signature was observed in patients with immune-mediated hepatitis but not in patients with rheumatic irAEs or toxicity-free controls. An IFN-γ-driven inflammatory profile was also detected in CSF from patients with CNS irAEs. Longitudinal analyses demonstrated that ICOS expression and IFN-γ-associated mediators closely tracked disease activity and normalized following clinical resolution. Single-cell transcriptomic analyses identified activated T-cell populations as the primary source of IFN-γ, whereas CXCL9, CXCL10, and CXCL11 were predominantly expressed by myeloid cells, supporting a T-cell–myeloid inflammatory circuit. Furthermore, selected T-cell clones underwent marked expansion during active disease.Conclusions CNS irAEs following dual CTLA-4/PD-1 blockade are associated with a distinct ICOS–IFN-γ immune signature characterized by activated T cells, enhanced IFN-γ signaling, and clonal T-cell expansion. The shared immune phenotype observed in CNS irAEs and immune-mediated hepatitis suggests a common pathogenic mechanism across these toxicities. These findings provide mechanistic insight into checkpoint inhibitor-associated CNS inflammation and identify ICOS + T cells and IFN-γ-associated mediators as candidate biomarkers for disease monitoring and potential therapeutic intervention.References Bjursten S, Pandita A, Zhao Z, Fröjd C, Ny L, Jensen C, et al. Early rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis. J Immunother Cancer. 2021;9(7).Bjursten S, Zhao Z, Al Remawi H, Studahl M, Pandita A, Simrén J, et al. Concentrations of S100B and neurofilament light chain in blood as biomarkers for checkpoint inhibitor-induced CNS inflammation. EBioMedicine 2024;100:104955.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0977