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
用于肿瘤学的精准现货型 NK 细胞疗法，采用逻辑门控基因回路
英文原题：Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits.
查看英文原题
Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits.
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中文摘要
急性髓系白血病（AML）是一种侵袭性疾病，预后较差（美国5年生存率为30.5%）。设计针对AML的细胞疗法具有挑战性，因为没有任何单一肿瘤相关抗原（TAA）在所有癌症亚群中均高表达。此外，TAA也表达于健康细胞，导致毒性风险。为解决这些靶向挑战，我们通过多输入基因回路工程化自然杀伤（NK）细胞，该回路包含由OR和NOT逻辑门控制的嵌合抗原受体（CAR）。OR门利用靶向FLT3和/或CD33的双价CAR杀伤从白血病干细胞到原始细胞的一系列AML细胞。NOT门利用靶向endomucin的抑制性CAR保护健康造血干细胞（HSC），endomucin是健康HSC特有的保护性抗原。具有联合OR-NOT基因回路的NK细胞可杀伤多种AML亚型并保护原代HSC，该回路在体内也有效。
展开英文摘要原文
Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis (5-year survival rate of 30. 5% in the United States). Designing cell therapies to target AML is challenging because no single tumor-associated antigen (TAA) is highly expressed on all cancer subpopulations.
Furthermore, TAAs are also expressed on healthy cells, leading to toxicity risk. To address these targeting challenges, we engineer natural killer (NK) cells with a multi-input gene circuit consisting of chimeric antigen receptors (CARs) controlled by OR and NOT logic gates. The OR gate kills a range of AML cells from leukemic stem cells to blasts using a bivalent CAR targeting FLT3 and/or CD33.
The NOT gate protects healthy hematopoietic stem cells (HSCs) using an inhibitory CAR targeting endomucin, a protective antigen unique to healthy HSCs. NK cells with the combined OR-NOT gene circuit kill multiple AML subtypes and protect primary HSCs, and the circuit also works in vivo.
论文信息
- 作者
- Frankel NW、Deng H、Yucel G、Gainer M、Leemans N、Lam A、Li Y、Hung M
- 第一作者单位
- Senti Biosciences, Inc., South San Francisco, CA 94080, USA. Electronic address: nicholas.frankel@sentibio.com.United States
- 通讯作者单位
- Senti Biosciences, Inc., South San Francisco, CA 94080, USA. Electronic address: brian.garrison@sentibio.com.United States
- 文献类型
- 非美国政府资助研究
- 期刊
- Cell reports2024 May 28
- 原文标识
- PubMed 38669141 · DOI 10.1016/j.celrep.2024.114145