Checkpoint blockade-related CNS adverse events are characterized by neurotoxic T helper cells with sustained neuroantigen reactivity
Cell Reports Medicine, 2026
Ma Y., Zhang A., Lin J., Ding F., Wang X., Wang W., Jian G., Zhang J., Zhu P., Ma Y., Lv J., Zheng H., Li J., Wu T., Zeng J., Jiang Y., Xu Y., Lyu X., Wang Y., Li Y., Liu N., Zheng Z., Niu Y., Guo Z., Fang N., Jiang W., Wang L., Chen J., Yuan M., Huang Q., Li J., Lu J., Chen B., Huang T., He T., Zhong G., Li R., Liu H., Weng S.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Neurology Immunotherapy | Pathophysiology | CSF |  Olink Target 96  Olink Explore 3072/384 |
Abstract
The immune-related adverse events of central nervous system (irAEs-CNS) are rare yet life-threatening complications arising from immune checkpoint inhibitor therapies, with no effective treatments. The intracranial immune landscape in irAE-CNS remains poorly characterized. Through longitudinal multi-omics profiling of cerebrospinal fluid from three independent clinical cohorts—combined with serial cerebral positron emission tomography/computed tomography (PET/CT) imaging, neurofunctional assessments, and 15-month clinical follow-up, we identify a defined proinflammatory memory T helper cell population specific to irAEs-CNS. These cells co-secrete six signature inflammatory mediators (poly6+ cells) linked to interleukin (IL)-17-driven pathways, exhibit persistent neuroantigen reactivity, and could induce neuron apoptosis. Notably, NMDAR1-specific poly6+ cells are correlated with intracranial inflammation states and clinical outcomes of the disease. Therapeutically, inhibition of IL-17—a key cytokine of poly6+ cells—significantly improves irAE-CNS outcomes without compromising overall survival rates. Our study uncovers neuroantigen-specific proinflammatory Th cells as central drivers of irAE-CNS pathogenesis, offering mechanistic insights and potential therapeutic targets for this debilitating condition.