TY  - JOUR
AU  - Lu, I-Na
AU  - Müller-Miny, Louisa
AU  - Krekeler, Carolin
AU  - Cheung, Phyllis Fung-Yi
AU  - Antonopoulou, Georgia
AU  - Jeibmann, Astrid
AU  - Schulte-Mecklenbeck, Andreas
AU  - Kerl, Kornelius
AU  - Call, Simon
AU  - Reicherts, Christian
AU  - Bleckmann, Annalen
AU  - Stelljes, Matthias
AU  - Lenz, Georg
AU  - Wiendl, Heinz
AU  - Zu Hörste, Gerd Meyer
AU  - Grauer, Oliver M
TI  - The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy.
JO  - Genome medicine
VL  - 17
IS  - 1
SN  - 1756-994X
CY  - London
PB  - BioMed Central
M1  - DKFZ-2025-01341
SP  - 71
PY  - 2025
AB  - Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common and potentially life-threatening complication of chimeric antigen receptor (CAR) T cell therapy. The underlying mechanisms of ICANS remain incompletely understood and are unlikely to be explained by cytokine excess alone.We analyzed paired peripheral blood and cerebrospinal fluid (CSF) samples from CAR T cell-treated patients who developed ICANS (n = 11) within 5-21 days post-infusion. ICANS severity was graded as follows: grade 1 (n = 3), grade 2 (n = 4), grade 3 (n = 1), and grade 4 (n = 3). Control samples were obtained from patients with idiopathic intracranial hypertension, functional neurological disorders, and multiple sclerosis. We employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to profile immune cell populations and performed multi-modal spatial transcriptomics and immunofluorescence on postmortem choroid plexus and brain tissue from a patient with fatal grade 4 ICANS.We identified a distinct population of proliferating, cytotoxic T cells characterized by CXCR6 expression, enriched in CD4 + CAR T cells and predominantly localized in ICANS CSF. These CXCR6 + T cells were largely absent from control CSF samples. Spatial mapping of postmortem brain tissue revealed widespread infiltration of myeloid cells and a striking spatial association between CXCR6 + T cells and CXCL16-expressing myeloid cells in both the choroid plexus and brain parenchyma. Notably, CSF levels of CXCL16 positively correlated with ICANS severity across the cohort, from grade 1 to grade 4.Our findings implicate the CXCL16/CXCR6 axis in the recruitment of cytotoxic CAR CD4 + T cells to the central nervous system (CNS) during ICANS. This interaction may be linked to neuroinflammatory processes and severity stratification in ICANS pathogenesis. These results provide a mechanistic rationale for exploring CXCL16/CXCR6 as a potential biomarker and therapeutic target in CAR T cell-associated neurotoxicity.
KW  - Humans
KW  - Receptors, CXCR6: metabolism
KW  - Receptors, CXCR6: genetics
KW  - Neurotoxicity Syndromes: etiology
KW  - Neurotoxicity Syndromes: metabolism
KW  - Chemokine CXCL16: metabolism
KW  - Chemokine CXCL16: genetics
KW  - Male
KW  - Receptors, Chimeric Antigen: metabolism
KW  - Immunotherapy, Adoptive: adverse effects
KW  - Female
KW  - Middle Aged
KW  - Adult
KW  - Aged
KW  - T-Lymphocytes: immunology
KW  - T-Lymphocytes: metabolism
KW  - Receptors, CXCR6 (NLM Chemicals)
KW  - Chemokine CXCL16 (NLM Chemicals)
KW  - CXCR6 protein, human (NLM Chemicals)
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
KW  - CXCL16 protein, human (NLM Chemicals)
KW  - cell-associated neurotoxicity (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40588764
C2  - pmc:PMC12210444
DO  - DOI:10.1186/s13073-025-01498-6
UR  - https://inrepo02.dkfz.de/record/302801
ER  -