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
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CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
命运调控的参与增强 LV/hu-IL-12 转导肉瘤中的 NK 细胞应答
英文原题：Fate control engagement augments NK cell responses in LV/hu-IL-12 transduced sarcoma.
查看英文原题
Fate control engagement augments NK cell responses in LV/hu-IL-12 transduced sarcoma.
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研究概要
mTMPK 命运控制的启用终止了转导肉瘤的 IL-12 产生并触发细胞死亡，但同时也增强了 NK 细胞介导的反应，这一反应与代谢应激激活表面配体诱导同时发生。
中文摘要
目的
研究拟启用突变型胸苷酸激酶（mTMPK）代谢命运控制系统调节全身炎症，并评估其对 NK 细胞效应功能的影响。
方法
通过慢病毒载体 LV/hu-IL-12_mTMPK 转导原代人肉瘤短期传代样本和细胞系，使其表达 IL-12 和一种与 AZT 相关的命运控制酶。研究评估转导肉瘤对 AZT 的反应，以及由此对 NK 细胞功能的调节，通过炎症细胞因子产生和细胞毒性进行测量。
结果
对转导后的短期传代原代人肉瘤以及人尤文肉瘤、骨肉瘤和横纹肌肉瘤细胞系给予 AZT，可阻断人 IL-12 的强效表达。激活命运控制后产生特异性、剂量依赖性细胞毒作用，通过代谢活性（WST-1）和细胞死亡（Incucyte）测定。尽管 IL-12 表达被阻断，NK 效应功能（IFN-γ 及细胞毒颗粒释放）仍显著增强，并与 NK 细胞活化配体优先诱导表达相关。
结论
启用 mTMPK 命运控制可终止转导肉瘤的 IL-12 产生并诱导细胞死亡，同时伴随代谢应激激活表面配体，增强 NK 细胞介导应答。启用命运控制或可提供一种新的免疫激活方法，以利用 NK 细胞清除癌症。
展开英文摘要原文
OBJECTIVES
We sought to engage the mutant thymidylate kinase (mTMPK) metabolic fate control system to regulate systemic inflammation and assess the impact on NK cell effector functions.
METHODS
Primary human sarcoma short-passage samples and cell lines were transduced with LV/hu-IL-12_mTMPK engineering expression of IL-12 and an AZT-associated fate control enzyme. We assessed transduced sarcoma responses to AZT engagement and subsequent modulation of NK cell functions as measured by inflammatory cytokine production and cytotoxicity.
RESULTS
AZT administration to transduced (LV/hu-IL-12_mTMPK) short-passage primary human sarcomas and human Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines, abrogated the robust expression of human IL-12. Fate control activation elicited a specific dose-dependent cytotoxic effect measured by metabolic activity (WST-1) and cell death (Incucyte). NK effector functions of IFN- and cytotoxic granule release were significantly augmented despite IL-12 abrogation. This correlated with preferentially induced expression of NK cell activation ligands.
CONCLUSIONS
mTMPK fate control engagement terminates transduced sarcoma IL-12 production and triggers cell death, but also augments an NK cell-mediated response coinciding with metabolic stress activating surface ligand induction. Fate control engagement could offer a novel immune activation method for NK cell-mediated cancer clearance.
论文信息
- 作者
- Rademacher MJ、Faber ML、Bone KM、Medin JA、Schloemer NJ
- 第一作者单位
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA.United States
- 通讯作者单位
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: nschloem@mcw.edu.United States
- 期刊
- Experimental and molecular pathology2024 Jun
- 原文标识
- PubMed 38729059 · DOI 10.1016/j.yexmp.2024.104898