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
非小细胞肺癌中的亚克隆免疫逃逸
英文原题：Subclonal immune evasion in non-small cell lung cancer.
查看英文原题
Subclonal immune evasion in non-small cell lung cancer.
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中文摘要
癌症对免疫治疗很少产生完全应答。虽然肿瘤由多个基因上不同的克隆组成，但由于无法从人类癌症中分离和扩增单个亚克隆，这是否影响免疫逃逸的潜力仍不清楚。在此，我们利用多区域TRACERx肺癌进化研究，建立了一个患者来源的类器官-T细胞共培养平台，能够在单克隆分辨率下对亚克隆免疫逃逸进行功能分析。我们从三名患者的11个不同肿瘤区域建立了类器官系，随后分离出81个单独的克隆亚系。与TIL（肿瘤浸润淋巴细胞）或自然杀伤（NK）细胞共培养，在全部3名患者中揭示了癌症内在性和亚克隆免疫逃逸。免疫逃逸亚克隆代表具有独特进化历史的基因上不同的谱系。这表明免疫逃逸和非逃逸亚克隆可以从同一肿瘤中分离出来，提示亚克隆肿瘤进化直接影响免疫逃逸。
展开英文摘要原文
Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers.
Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid - T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution.
We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients.
Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.
论文信息
- 作者
- Dijkstra KK、Vendramin R、Karagianni D、Witsen M、Gálvez-Cancino F、Hill MS、Foster KA、Barbè V
- 第一作者单位
- Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Oncode Institute, Utrecht, the Netherlands. Electronic address: k.dijkstra@nki.nl.Netherlands
- 通讯作者单位
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK. Electronic address: charles.swanton@crick.ac.uk.United Kingdom
- 期刊
- Cancer cell2025 Oct 13
- 原文标识
- PubMed 40614739 · DOI 10.1016/j.ccell.2025.06.012