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
英文原题:Induction of γδT cells from HSC-enriched BMCs co-cultured with iPSC-derived thymic epithelial cells.
Induction of γδT cells from HSC-enriched BMCs co-cultured with iPSC-derived thymic epithelial cells.
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携带γδ抗原受体的T细胞已被研究作为多种疾病的潜在治疗方法,包括恶性肿瘤。然而,γδT细胞的临床应用一直受到其在体内相对低丰度以及体外诱导其从造血干细胞(HSCs)分化所面临的技术困难的阻碍。
在此,我们描述了一种通过将富含HSC的骨髓细胞(HSC-eBMCs)与源自诱导多能干细胞(iPSCs)的诱导性胸腺上皮细胞(iTECs)共培养来生成小鼠γδT细胞的新方法。
我们使用来自CD45.1同源C57BL/6小鼠的BMCs,以将其与表达CD45.2的iPSCs区分开来。我们发现,将HSC-eBMCs和iTECs用IL-2 + IL-7培养长达21天后,可诱导出表达广泛Vγ和Vδ T细胞受体库的CD45.1 + γδT细胞。
值得注意的是,诱导产生的淋巴细胞中几乎没有或没有αβT细胞、NK1.1 + NK 细胞或B220 + B细胞。将诱导产生的γδT细胞过继转移至荷白血病小鼠后,可显著减少肿瘤生长并延长小鼠生存期,且没有明显副作用,如致瘤性和自身免疫性疾病。这种新方法表明,它也可用于生产用于临床应用的人γδT细胞。
T cells bearing γδ antigen receptors have been investigated as potential treatments for several diseases, including malignant tumours.
However, the clinical application of γδT cells has been hampered by their relatively low abundance in vivo and the technical difficulty of inducing their differentiation from hematopoietic stem cells (HSCs) in vitro.
Here, we describe a novel method for generating mouse γδT cells by co-culturing HSC-enriched bone marrow cells (HSC-eBMCs) with induced thymic epithelial cells (iTECs) derived from induced pluripotent stem cells (iPSCs).
We used BMCs from CD45. 1 congenic C57BL/6 mice to distinguish them from iPSCs, which expressed CD45. 2.
We showed that HSC-eBMCs and iTECs cultured with IL-2 + IL-7 for up to 21 days induced CD45. 1 + γδT cells that expressed a broad repertoire of Vγ and Vδ T-cell receptors.
Notably, the induced lymphocytes contained few or no αβT cells, NK1. 1 + natural killer cells, or B220 + B cells. Adoptive transfer of the induced γδT cells to leukemia-bearing mice significantly reduced tumour growth and prolonged mouse survival with no obvious side effects, such as tumorigenesis and autoimmune diseases. This new method suggests that it could also be used to produce human γδT cells for clinical applications.
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