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
DOT1L 维持 NK 细胞表型和功能以实现最佳肿瘤控制
英文原题：DOT1L maintains NK cell phenotype and function for optimal tumor control.
查看英文原题
DOT1L maintains NK cell phenotype and function for optimal tumor control.
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中文摘要
组蛋白甲基转移酶（HMTs）在基因调控和功能中至关重要，但其在肿瘤微环境（TME）中自然杀伤（NK）细胞生物学中的作用仍很大程度上未知。我们证明，HMT DOT1L限制了NK细胞向CD49a+ CD49b+ intILC1的转化，该亚群可在TME中响应转化生长因子（TGF）-β刺激而被观察到，并与肿瘤控制受损相关。在表达NKp46的细胞中敲除Dot1l揭示了其在维持NK细胞表型和功能中的关键作用。即使在没有TGF-β的情况下，DOT1L缺失也会使NK细胞偏向intILC1s。在转录水平上，DOT1L缺失的NK细胞与intILC1s和ILC1s高度相似，这与NK细胞反应改变和实体瘤控制受损相关。这些发现加深了我们对NK细胞生物学的理解，并可能为在癌症过继性NK细胞治疗中防止NK细胞向intILC1s转化提供策略。
展开英文摘要原文
Histone methyltransferases (HMTs) are crucial in gene regulation and function, yet their role in natural killer (NK) cell biology within the tumor microenvironment (TME) remains largely unknown.
We demonstrate that the HMT DOT1L limits NK cell conversion to CD49a+ CD49b+ intILC1, a subset that can be observed in the TME in response to stimulation with transforming growth factor (TGF)-β and is correlated with impaired tumor control.
Deleting Dot1l in NKp46-expressing cells reveals its pivotal role in maintaining NK cell phenotype and function. Loss of DOT1L skews NK cells toward intILC1s even in the absence of TGF-β. Transcriptionally, DOT1L-null NK cells closely resemble intILC1s and ILC1s, correlating with altered NK cell responses and impaired solid tumor control.
These findings deepen our understanding of NK cell biology and could inform approaches to prevent NK cell conversion to intILC1s in adoptive NK cell therapies for cancer.
论文信息
- 作者
- Sudholz H、Schuster IS、Foroutan M、Sng X、Andoniou CE、Doan A、Camilleri T、Shen Z
- 第一作者单位
- Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia.Australia
- 通讯作者单位
- Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia. Electronic address: sebastian.scheer@lih.lu.Australia
- 文献类型
- 非美国政府资助研究
- 期刊
- Cell reports2024 Jun 25
- 原文标识
- PubMed 38865244 · DOI 10.1016/j.celrep.2024.114333