CD81 通过阻断 CD274/PD-L1 的选择性自噬降解驱动放射抵抗性胶质母细胞瘤的免疫逃逸
CD81 drives immune evasion in radioresistant glioblastoma by blocking selective autophagic degradation of CD274/PD-L1.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
由微外显子跳跃定义的 NRCAM 变体是高级别胶质瘤中可靶向的细胞表面蛋白质异构体
英文原题：NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas.
查看英文原题
NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
为克服儿童高级别胶质瘤（pHGG）已知肿瘤特异性表面抗原不足的问题，研究比较了pHGG与正常脑组织样本的剪接模式。在影响细胞外蛋白结构域的可变剪接事件中，最普遍的改变是跳跃≤30个核苷酸的外显子。其中若干被跳跃的微外显子位于L1免疫球蛋白细胞黏附分子（IgCAM）家族成员中，例如神经细胞黏附分子（NRCAM）。整体及单核短读长、长读长RNA测序显示，几乎所有pHGG样本中的NRCAM微外显子5和19均发生一致性跳跃。
重要的是，Δex5Δex19型（而非全长型）NRCAM蛋白异构体对pHGG细胞体外迁移和侵袭以及体内肿瘤生长至关重要。研究开发了一种可选择性识别Δex5Δex19 NRCAM的单克隆抗体，并证明用该抗体“标记”pHGG细胞后，可被表达FcRI型通用免疫受体的T细胞杀伤。
因此，pHGG特异性NRCAM以及可能的其他L1-IgCAM蛋白异构体，是过继免疫疗法有前景且高度选择性的靶点。
展开英文摘要原文
To overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns in pHGGs and normal brain samples. Among alternative splicing events affecting extracellular protein domains, the most pervasive alteration was the skipping of ≤30-nt-long exons.
Several of these skipped microexons mapped to L1-immunoglobulin cell adhesion molecule (IgCAM) family members, such as neuronal CAM (NRCAM). Bulk and single-nuclei short- and long-read RNA-seq revealed uniform skipping of NRCAM microexons 5 and 19 in virtually every pHGG sample.
Importantly, the Δex5Δex19 (but not the full-length) NRCAM proteoform was essential for pHGG cell migration and invasion in vitro and tumor growth in vivo.
We developed a monoclonal antibody selective for Δex5Δex19 NRCAM and demonstrated that "painting" pHGG cells with this antibody enables killing by T cells armed with an FcRI-based universal immune receptor.
Thus, pHGG-specific NRCAM and possibly other L1-IgCAM proteoforms are promising and highly selective targets for adoptive immunotherapies.
论文信息
- 作者
- Sehgal P、Naqvi AS、Higgins M、Liu J、Harvey K、Jarroux J、Kim T、Mankaliye B
- 第一作者单位
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.United States
- 通讯作者单位
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: andreit@pennmedicine.upenn.edu.United States
- 期刊
- Cell reports2025 Aug 26
- 原文标识
- PubMed 40782352 · DOI 10.1016/j.celrep.2025.116099
在 PubMed 查看 → 出版商原文（DOI） 全文 PDF（PMC）· 可下载 治疗专题与资料阅读指南 资料来源与翻译说明 报告译文或资料问题 →