{
  "abstract": "Background Immune checkpoint inhibitor (ICI) therapies present a pillar of modern cancer therapy but can cause neurological immune-related adverse events (n-irAEs), of which up to 35% are severe or even fatal. However, the detailed immunological mechanisms and risk factors underlying n-irAEs remain largely unknown. Here, we leveraged single-cell genomics to dissect immune cell type, state, and clonal heterogeneity associated with n-irAEs.Methods We performed coupled single-cell RNA sequencing and T cell receptor (TCR) profiling on peripheral blood cells of 17 patients with cancer receiving ICI therapy, including 8 patients with acute neurotoxicity. This approach enabled integrated analyses of immune cell states and T cell clonality linked to ICI-induced n-irAEs.Results We profiled 186 435 immune cells and conducted pseudotime analyses, revealing that patients with n-irAEs, compared with controls, present with clonally expanded CD4 + cytotoxic T lymphocytes (CD4+ CTLs) with an n-irAE-specific effector gene expression profile. These T cells predominantly belong to a select set of expanded clonal families and express genes linked to antigen-induced activation, cell lysis, and neuroinflammation. Moreover, they highly express CXCR3 (FC=2.03 compared with control CD4+ CTLs, with a false discovery rate=7.7×10⁻⁴), encoding the chemokine receptor of CXCL10, previously nominated as a biomarker for severe ICI therapy-induced n-irAEs with concomitant multiple organ system toxicity.Conclusions Overall, our study highlights the expansion and activation of CD4 + CTLs in ICI-induced neurotoxicity, proposing these cells as potential targets for developing new biomarkers and therapeutic strategies to improve patient outcomes.",
  "authors": [
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany"
      ],
      "name": "Ambre Manon Giguelay"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany",
        "Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany"
      ],
      "name": "Patrick Maschmeyer"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Leonie Müller-Jensen"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Christian Schinke"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Einstein Center for Neurosciences Berlin (ECN) at Charité - Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Smilla K Maierhof"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany"
      ],
      "name": "Natasha Nambiar"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany",
        "Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany",
        "Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Manpreet Meyer"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Petra Huehnchen"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Wolfgang Boehmerle"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany",
        "Charité Universitätsmedizin Berlin, Center for Stroke Research Berlin, Berlin, Germany",
        "German Center for Neurodegenerative Diseases (DZNE), partner site Berlin, Berlin, Germany",
        "German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany",
        "German Center for Mental Health (DZPG), partner site Berlin, Berlin, Germany"
      ],
      "name": "Matthias Endres"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Samuel Knauss"
    },
    {
      "affiliations": [
        "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany"
      ],
      "name": "Leif S. Ludwig"
    }
  ],
  "title": "Clonally expanded effector CD4+ cytotoxic T lymphocytes are associated with severe neurological adverse events after immune checkpoint inhibitor therapy",
  "uid": "3ddd6944-5e6e-5a9d-8b09-b34f6d1468f2"
}