Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies.,Cell

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Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies.
Cell ( IF 64.5 ) Pub Date : 2020-09-21 , DOI: 10.1016/j.cell.2020.08.022
Kevin R Parker ₁ , Denis Migliorini ₂ , Eric Perkey ₃ , Kathryn E Yost ₁ , Aparna Bhaduri ₄ , Puneet Bagga ₅ , Mohammad Haris ₆ , Neil E Wilson ₅ , Fang Liu ₇ , Khatuna Gabunia ₇ , John Scholler ₇ , Thomas J Montine ₈ , Vijay G Bhoj ₉ , Ravinder Reddy ₅ , Suyash Mohan ₅ , Ivan Maillard ₁₀ , Arnold R Kriegstein ₄ , Carl H June ₁₁ , Howard Y Chang ₁₂ , Avery D Posey ₁₃ , Ansuman T Satpathy ₁₄

Affiliation

Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA.
Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Translational Research in Onco-Hematology and Department of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
Graduate Program in Cellular and Molecular Biology and Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA; Division of Hematology-Oncology, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Functional and Molecular Imaging Laboratory, Research Branch, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar.
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Division of Hematology-Oncology, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.

中文翻译：

单细胞分析鉴定表达 CD19 的脑壁细胞作为 CAR-T 免疫疗法的潜在肿瘤外靶点。

CD19导向的免疫疗法在临床上对治疗B细胞恶性肿瘤有效，但也引起高发生率的神经毒性。使用嵌合抗原受体 (CAR) T 细胞或双特异性 T 细胞接合器 (BiTE) 抗体治疗的一部分患者表现出严重的神经毒性，包括与 T 细胞浸润大脑相关的致命性脑水肿。在此，我们报道了围绕内皮细胞并对血脑屏障完整性至关重要的壁细胞表达 CD19。我们使用单细胞 RNA 测序数据识别脑壁细胞中的CD19表达，并在蛋白质水平上确认血管周围染色。大脑中的CD19表达在发育早期随着壁细胞谱系的出现而开始，并在整个成年期持续存在于大脑区域。小鼠壁细胞表现出较低水平的Cd19表达，表明神经毒性的临床前动物模型存在局限性。这些数据表明了 CD19 定向疗法中神经毒性的靶向机制，并强调了人类单细胞图谱在设计免疫疗法中的效用。

更新日期：2020-10-02

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