Persistent Neuro-Antigen-Reactive Th17 Cells Induce IL-17-Dependent Neurotoxicity

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer outcomes but can induce immune-related adverse events (irAEs) that limit therapy. Central nervous system irAEs (irAE-CNS) are rare, often corticosteroid-refractory, and lead to disabling neurological sequelae. Their immunopathogenesis remains poorly understood, hindering effective interventions. We aimed to define the immune mechanisms underlying irAE-CNS and identify therapeutic targets using multi-omics profiling and longitudinal clinical correlation. Methods: We analyzed cerebrospinal fluid (CSF) from three independent irAE-CNS cohorts and controls (autoimmune encephalitis, CNS infection). Multi-omics profiling integrated OLINK proteomics, single-cell secretome and transcriptome analysis, and paired VDJ-TCR repertoire sequencing with FDG-PET/CT imaging, neurofunctional testing, and 15-month follow-up. Unsupervised clustering (Seurat) and clonotype mapping (CellRanger/IGBLAST) were used to define cell phenotypes and track longitudinal persistence. Neuroantigen reactivity was validated via MHC-multimer sorting and peptide libraries derived from neuronal surface proteins, including NMDAR1. Functional assays assessed T-cell-mediated neuronal cytotoxicity and the effects of IL-17 blockade. Results: We identified a distinct population of CD4+CD137+PD-1+ effector-memory T-helper cells (Poly6+ Th cells) enriched in irAE-CNS, co-secreting IL-17A, TNFRSF9, CCL11, MCP-1, MCP-4, and Granzyme B, defining a polyfunctional Th17-like signature. Poly6+ Th-cell frequency correlated with intracranial FDG-PET hypermetabolism especially within limbic regions, and with cognitive decline. Single-cell RNA-seq revealed stable RORC+IL23R+GZMB+ transcriptional profiles, and VDJ analysis showed persistent, antigen-driven clonal expansion. Dominant clonotypes targeted NMDAR1 epitopes (notably EERITGINDPRLRNP), confirming neuroantigen-specific persistence. In co-culture assays, Poly6+ Th cells induced neuronal apoptosis via IL-17-dependent mechanisms. In patients treated with IL-17 blockade, neurological symptoms and intracranial inflammation improved significantly without reducing ICI antitumor efficacy. Conclusions: irAE-CNS is driven by persistent, NMDAR1-reactive Th17-like effector-memory cells that mediate IL-17-dependent neurotoxicity. These findings reveal a mechanistic basis for selective cytokine blockade to alleviate CNS autoimmunity while maintaining checkpoint efficacy, providing a framework for biomarker-guided management of ICI-associated toxicities. Citation Format: Yifei Ma, Jingyao Zhang, Fadian Ding, Ao Zhang, Jun Lv, Xinjia Wang, Weidong Wang, Guangmin Jian, Pengfei Zhu, Yue Ma, Jiacai Lin, Denghan Zhang, Guanqing Zhong, Rui Li, Haizhou Liu, Shangeng Weng. Persistent neuro-antigen-reactive Th17 cells drive IL-17-dependent neurotoxicity in CNS immune-related adverse events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6744.