The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy
Abstract Background 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 cytoki...
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BMC
2025-06-01
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| Series: | Genome Medicine |
| Online Access: | https://doi.org/10.1186/s13073-025-01498-6 |
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| author | I-Na Lu Louisa Müller-Miny Carolin Krekeler Phyllis Fung-Yi Cheung Georgia Antonopoulou Astrid Jeibmann Andreas Schulte-Mecklenbeck Kornelius Kerl Simon Call Christian Reicherts Annalen Bleckmann Matthias Stelljes Georg Lenz Heinz Wiendl Gerd Meyer zu Hörste Oliver M. Grauer |
| author_facet | I-Na Lu Louisa Müller-Miny Carolin Krekeler Phyllis Fung-Yi Cheung Georgia Antonopoulou Astrid Jeibmann Andreas Schulte-Mecklenbeck Kornelius Kerl Simon Call Christian Reicherts Annalen Bleckmann Matthias Stelljes Georg Lenz Heinz Wiendl Gerd Meyer zu Hörste Oliver M. Grauer |
| author_sort | I-Na Lu |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| format | Article |
| id | doaj-art-a9dc471607f24ffcbe922b745b599b20 |
| institution | Kabale University |
| issn | 1756-994X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj-art-a9dc471607f24ffcbe922b745b599b202025-08-20T04:02:56ZengBMCGenome Medicine1756-994X2025-06-0117111410.1186/s13073-025-01498-6The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapyI-Na Lu0Louisa Müller-Miny1Carolin Krekeler2Phyllis Fung-Yi Cheung3Georgia Antonopoulou4Astrid Jeibmann5Andreas Schulte-Mecklenbeck6Kornelius Kerl7Simon Call8Christian Reicherts9Annalen Bleckmann10Matthias Stelljes11Georg Lenz12Heinz Wiendl13Gerd Meyer zu Hörste14Oliver M. Grauer15Department of Neurology With Institute of Translational Neurology, University Hospital MünsterDepartment of Neurology With Institute of Translational Neurology, University Hospital MünsterDepartment of Medicine A, Hematology, Oncology, and Pneumology, University Hospital MünsterSpatiotemporal Tumor Heterogeneity, German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital EssenBridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-EssenInstitute of Neuropathology, University Hospital MünsterDepartment of Neurology With Institute of Translational Neurology, University Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Children’s Hospital MünsterDepartment of Medicine A, Hematology, Oncology, and Pneumology, University Hospital MünsterDepartment of Medicine A, Hematology, Oncology, and Pneumology, University Hospital MünsterDepartment of Medicine A, Hematology, Oncology, and Pneumology, University Hospital MünsterDepartment of Medicine A, Hematology, Oncology, and Pneumology, University Hospital MünsterDepartment of Medicine A, Hematology, Oncology, and Pneumology, University Hospital MünsterDepartment of Neurology With Institute of Translational Neurology, University Hospital MünsterDepartment of Neurology With Institute of Translational Neurology, University Hospital MünsterDepartment of Neurology With Institute of Translational Neurology, University Hospital MünsterAbstract Background 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. Methods 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. Results 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. Conclusions 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.https://doi.org/10.1186/s13073-025-01498-6 |
| spellingShingle | I-Na Lu Louisa Müller-Miny Carolin Krekeler Phyllis Fung-Yi Cheung Georgia Antonopoulou Astrid Jeibmann Andreas Schulte-Mecklenbeck Kornelius Kerl Simon Call Christian Reicherts Annalen Bleckmann Matthias Stelljes Georg Lenz Heinz Wiendl Gerd Meyer zu Hörste Oliver M. Grauer The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy Genome Medicine |
| title | The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy |
| title_full | The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy |
| title_fullStr | The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy |
| title_full_unstemmed | The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy |
| title_short | The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy |
| title_sort | cxcl16 cxcr6 axis is linked to immune effector cell associated neurotoxicity in chimeric antigen receptor car t cell therapy |
| url | https://doi.org/10.1186/s13073-025-01498-6 |
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