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
模拟对白细胞介素-21 的应答以指导 NK 细胞免疫治疗
英文原题：Modeling the response to interleukin-21 to inform natural killer cell immunotherapy.
查看英文原题
Modeling the response to interleukin-21 to inform natural killer cell immunotherapy.
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中文摘要
自然杀伤（NK）细胞正在成为癌症治疗的新兴手段。多种不同的细胞因子被用于生成用于过继免疫治疗的NK细胞，包括可溶性白细胞介素（IL）-2、IL-12、IL-15和IL-18，以及膜结合型IL-21。这些细胞因子通过整合信号转导与转录激活因子（STAT）和核因子-κB（NF-κB）通路来驱动NK细胞活化，这些通路相互重叠并协同作用，使得预测用于增殖和细胞毒性的最佳细胞因子组合具有挑战性。
我们将多种细胞因子组合培养的NK细胞的功能检测与使用特征选择和机制回归模型的数学建模相结合。我们的回归模型成功预测了不同细胞因子组合下NK细胞的增殖，并揭示了活化STAT和NF-κB转录因子在启动阶段和启动后阶段之间的协同作用。在NK细胞培养的启动阶段使用可溶性IL-21可改善NK细胞增殖，同时不损害针对肝细胞癌细胞系的细胞毒性潜力或干扰素γ分泌。
我们的工作为探究用于癌症免疫治疗的NK细胞增殖和活化提供了一个整合性框架。
展开英文摘要原文
Natural killer (NK) cells are emerging agents for cancer therapy. Several different cytokines are used to generate NK cells for adoptive immunotherapy including interleukin (IL)-2, IL-12, IL-15 and IL-18 in solution, and membrane-bound IL-21. These cytokines drive NK cell activation through the integration of signal transducers and activators of transcription (STAT) and nuclear factor-kappa B (NF- B) pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations for both proliferation and cytotoxicity.
We integrated functional assays for NK cells cultured in a variety of cytokine combinations with mathematical modeling using feature selection and mechanistic regression models.
Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy of activated STATs and NF- B transcription factors between priming and post-priming phases. The use of IL-21 in solution in the priming of NK cell culture resulted in an improved NK cell proliferation, without compromising cytotoxicity potential or interferon gamma secretion against hepatocellular carcinoma cell lines.
Our work provides an integrative framework for interrogating NK cell proliferation and activation for cancer immunotherapy.
论文信息
- 作者
- Nayak I、Biondo R、Stewart WC、Fulton RJ、Möker N、Zhang C、Khakoo SI、Das J
- 单位
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.United States
- 期刊
- Immunology and cell biology2025 Feb
- 原文标识
- PubMed 39865344 · DOI 10.1111/imcb.12848
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