RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
三阴性乳腺癌中靶向 NKG2DL 的双特异性 NKG2D-CD16 和 NKG2D-CD3 融合蛋白
英文原题：Targeting NKG2DL with Bispecific NKG2D-CD16 and NKG2D-CD3 Fusion Proteins on Triple-Negative Breast Cancer.
查看英文原题
Targeting NKG2DL with Bispecific NKG2D-CD16 and NKG2D-CD3 Fusion Proteins on Triple-Negative Breast Cancer.
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
三阴性乳腺癌（TNBC）是一种侵袭性特别强的乳腺癌亚型，对常规全身治疗缓解率较低，复发率较高。NK 细胞组 2D 配体（NKG2DL）家族成员表达于癌细胞上，但通常不表达于健康组织，因此是新型免疫疗法有前景的肿瘤抗原。我们开发了双特异性融合蛋白（BFP），由可靶向多种 NKG2DL 的 NKG2D 受体结构域与抗 CD3（NKG2D-CD3）或抗 CD16（NKG2D-CD16）Fab 片段融合构成。首先，我们分析了 TNBC 细胞系中 NKG2DL（MICA、MICB、ULBP1–4）的表达，发现 MICA 和 ULBP2 的表面表达最高。利用 NKG2D-CD3/CD16 靶向 TNBC 细胞，可有效活化 NK 和 T 细胞，诱导其脱颗粒和细胞因子释放，并杀伤 TNBC 细胞。此外，对目前正在接受化疗的 TNBC 患者，其外周血单个核细胞（PBMC）经 NKG2D-CD3/CD16 刺激后，NK 和 T 细胞活化以及肿瘤细胞杀伤均显著提高。结论：BFP 可活化并引导健康人和 TNBC 患者自身 NK 细胞及 T 细胞靶向 TNBC 细胞，从而有效清除肿瘤细胞。因此，基于 NKG2D 的 NK 和 T 细胞衔接器可能成为 TNBC 患者治疗选择的有价值补充。
展开英文摘要原文
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches.
We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti-CD3 (NKG2D-CD3) or anti-CD16 (NKG2D-CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1-4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D-CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells.
Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D-CD3/CD16.
In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells.
Therefore, NKG2D-based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients.
论文信息
- 作者
- Kaidun P、Holzmayer SJ、Greiner SM、Seller A、Tegeler CM、Hagelstein I、Mauermann J、Engler T
- 单位
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, 72076 Tuebingen, Germany.Germany
- 期刊
- International journal of molecular sciences2023 Aug 24
- 原文标识
- PubMed 37685962 · DOI 10.3390/ijms241713156
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 →