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| Item Type: | Article |
|---|---|
| Title: | Clonally expanded effector CD4(+) cytotoxic T lymphocytes are associated with severe neurological adverse events after immune checkpoint inhibitor therapy |
| Creators Name: | Giguelay, Ambre Manon, Maschmeyer, Patrick, Müller-Jensen, Leonie, Schinke, Christian, Maierhof, Smilla K., Nambiar, Natasha, Meyer, Manpreet, Huehnchen, Petra, Boehmerle, Wolfgang, Endres, Matthias, Knauss, Samuel and Ludwig, Leif S. |
| 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. |
| Keywords: | CD4-Positive T-Lymphocytes, Cytotoxic T-Lymphocytes, Immune Checkpoint Inhibitors, Neoplasms, Nervous System Diseases |
| Source: | Journal for ImmunoTherapy of Cancer |
| ISSN: | 2051-1426 |
| Publisher: | BMJ Publishing Group |
| Volume: | 13 |
| Number: | 10 |
| Page Range: | e012350 |
| Date: | 30 October 2025 |
| Official Publication: | https://doi.org/10.1136/jitc-2025-012350 |
| PubMed: | View item in PubMed |
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