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@ARTICLE{Lu:302801,
      author       = {I.-N. Lu and L. Müller-Miny and C. Krekeler and P. F.
                      Cheung$^*$ and G. Antonopoulou and A. Jeibmann and A.
                      Schulte-Mecklenbeck and K. Kerl and S. Call and C. Reicherts
                      and A. Bleckmann and M. Stelljes and G. Lenz and H. Wiendl
                      and G. M. Zu Hörste and O. M. Grauer},
      title        = {{T}he {CXCL}16/{CXCR}6 axis is linked to immune effector
                      cell-associated neurotoxicity in chimeric antigen receptor
                      ({CAR}) {T} cell therapy.},
      journal      = {Genome medicine},
      volume       = {17},
      number       = {1},
      issn         = {1756-994X},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2025-01341},
      pages        = {71},
      year         = {2025},
      abstract     = {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.},
      keywords     = {Humans / Receptors, CXCR6: metabolism / Receptors, CXCR6:
                      genetics / Neurotoxicity Syndromes: etiology / Neurotoxicity
                      Syndromes: metabolism / Chemokine CXCL16: metabolism /
                      Chemokine CXCL16: genetics / Male / Receptors, Chimeric
                      Antigen: metabolism / Immunotherapy, Adoptive: adverse
                      effects / Female / Middle Aged / Adult / Aged /
                      T-Lymphocytes: immunology / T-Lymphocytes: metabolism /
                      Receptors, CXCR6 (NLM Chemicals) / Chemokine CXCL16 (NLM
                      Chemicals) / CXCR6 protein, human (NLM Chemicals) /
                      Receptors, Chimeric Antigen (NLM Chemicals) / CXCL16
                      protein, human (NLM Chemicals) / cell-associated
                      neurotoxicity (NLM Chemicals)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40588764},
      pmc          = {pmc:PMC12210444},
      doi          = {10.1186/s13073-025-01498-6},
      url          = {https://inrepo02.dkfz.de/record/302801},
}