Clonally expanded effector CD4+ cytotoxic T lymphocytes are associated with severe neurological adverse events after immune checkpoint inhibitor therapy
 

Identifier:

PMID: 41167637
PMCID: PMC12574404
DOI: 10.1136/jitc-2025-012350

 

Authors:

Ambre Manon Giguelay1,2,*, Patrick Maschmeyer1,2,3,*, Leonie Müller- Jensen1,4, Christian Schinke1,4, Smilla K Maierhof1,4,5, Natasha Nambiar1,2, Manpreet Meyer1,2,6,7, Petra Huehnchen1,4,8, Wolfgang Boehmerle1,4,8, Matthias Endres1,4,8,9,10,11,12, Samuel Knauss1,4,+, Leif S. Ludwig1,2,+

*equal contribution (first authorship)

+correspdonding authors

 

Author Affiliations:

1 Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
2 Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
3 Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany
4 Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
5 Einstein Center for Neurosciences Berlin (ECN) at Charité – Universitätsmedizin Berlin, Berlin, Germany
6 Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany
7 Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
8 NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany
9 Charité Universitätsmedizin Berlin, Center for Stroke Research Berlin, Berlin, Germany
10 German Center for Neurodegenerative Diseases (DZNE), partner site Berlin, Berlin, Germany
11 German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
12 German Center for Mental Health (DZPG), partner site Berlin, Berlin, Germany

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.