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
抗肿瘤应答过程中多功能 NK 细胞衔接器的表征与比较分析
英文原题：Characterization and comparative analysis of multifunctional natural killer cell engagers during antitumor responses.
查看英文原题
Characterization and comparative analysis of multifunctional natural killer cell engagers during antitumor responses.
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中文摘要
T细胞衔接器（TCE）是具有变革意义的肿瘤治疗药物，但因可诱发细胞因子释放综合征（CRS），其应用受到限制。与T细胞相比，自然杀伤（NK）细胞活化后产生的细胞因子较少，因此研究者开始探索NK细胞衔接器（NKCE）。然而，NK细胞为何较少分泌肿瘤坏死因子（TNF）等细胞因子，以及NKCE与TCE直接比较时的表现如何，仍不清楚。我们报告，与T细胞相比，NK细胞对TNF的运输和加工减少。系统性的开发和基准比较研究显示，可通过使NKCE接合多个活化受体并整合白细胞介素-2（IL-2），优化其效力和持久性。此外，在动物肿瘤模型中对NKCE、IL-2和TCE治疗进行比较，发现它们具有共同及各自独特的治疗获益。我们的结果为开发多功能NKCE提供了设计蓝图，这类药物有望成为现有TCE治疗的替代方案。
展开英文摘要原文
T cell engagers (TCEs) are transformational oncology therapies but are limited in use due to the induction of cytokine release syndrome (CRS). In comparison to T cells, natural killer (NK) cells produce fewer cytokines upon activation, leading to the exploration of NK cell engagers (NKCEs).
However, why NK cells secrete fewer cytokines, such as tumor necrosis factor (TNF), and how NKCEs perform directly against TCEs remains unclear.
Here, we report that relative to T cells, NK cells have reduced trafficking and processing of TNF. Systematic development and benchmarking studies show that NKCEs can be optimized to engage multiple activating receptors and incorporate interleukin (IL)-2, thereby increasing their potency and durability.
Furthermore, comparative studies of NKCE, IL-2, and TCE therapy in animal tumor models reveal both common and distinct therapeutic benefits.
Our results provide a blueprint for the development of multifunctional NKCEs, which may serve as an alternative to current TCE therapies.
论文信息
- 作者
- Lin H、Case R、Wei KY、Eres I、Alba BM、Kaner J、Wu YC、Yamawaki TM
- 第一作者单位
- Amgen Research, South San Francisco, CA 94080, USA; Amgen R&D Postdoctoral Fellows Program, South San Francisco, CA 94080, USA.United States
- 通讯作者单位
- Amgen Research, South San Francisco, CA 94080, USA. Electronic address: wdeng01@amgen.com.United States
- 文献类型
- 对照研究
- 期刊
- Cell reports. Medicine2025 May 20
- 原文标识
- PubMed 40318632 · DOI 10.1016/j.xcrm.2025.102117
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