The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy.

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
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
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引用次数: 0

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.

在嵌合抗原受体(CAR) T细胞治疗中,CXCL16/CXCR6轴与免疫效应细胞相关的神经毒性有关。
背景:免疫效应细胞相关神经毒性综合征(ICANS)是嵌合抗原受体(CAR) T细胞治疗的一种常见且可能危及生命的并发症。ICANS的潜在机制尚不完全清楚,也不太可能仅用细胞因子过量来解释。方法:我们分析了CAR - T细胞治疗后5-21天内发生ICANS的患者(n = 11)的外周血和脑脊液(CSF)样本。ICANS的严重程度分为:1级(n = 3)、2级(n = 4)、3级(n = 1)、4级(n = 3)。对照样本来自特发性颅内高压、功能性神经障碍和多发性硬化症患者。我们使用单细胞RNA测序(scRNA-seq)和流式细胞术来分析免疫细胞群,并对致命的4级ICANS患者的死后脉络丛和脑组织进行多模态空间转录组学和免疫荧光。结果:我们发现了一种独特的增殖细胞毒性T细胞群,其特征是CXCR6表达,富集于CD4 + CAR - T细胞,主要定位于ICANS CSF。这些CXCR6 + T细胞在对照CSF样本中基本缺失。死后脑组织的空间定位显示髓样细胞广泛浸润,并且CXCR6 + T细胞和表达cxcl16的髓样细胞在脉络丛和脑实质中存在显著的空间关联。值得注意的是,在整个队列中,CXCL16的CSF水平与ICANS严重程度呈正相关,从1级到4级。结论:我们的研究结果表明,在ICANS期间,CXCL16/CXCR6轴参与了细胞毒性CAR - CD4 + T细胞向中枢神经系统(CNS)的募集。这种相互作用可能与ICANS发病机制中的神经炎症过程和严重程度分层有关。这些结果为探索CXCL16/CXCR6作为CAR - T细胞相关神经毒性的潜在生物标志物和治疗靶点提供了机制基础。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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