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
用于过继细胞治疗的扩增 NK 细胞保持克隆多样性并包含长寿命记忆样 NK 细胞群体
英文原题：Expanded NK cells used for adoptive cell therapy maintain diverse clonality and contain long-lived memory-like NK cell populations.
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Expanded NK cells used for adoptive cell therapy maintain diverse clonality and contain long-lived memory-like NK cell populations.
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中文摘要
多项探索过继性自然杀伤（NK）细胞治疗癌症潜力的临床试验，采用饲养细胞进行体外扩增以获得大量NK细胞。我们此前利用恒河猴模型，在移植后对由条形码转导的CD34⁺干细胞和祖细胞产生的NK细胞子代进行克隆追踪。本研究使用带条形码的恒河猴NK细胞，考察与临床制备人NK细胞相似的培养方案在体外扩增过程中如何改变NK细胞克隆谱系模式；培养方案包括使用经照射的淋巴母细胞样细胞系（LCL）饲养细胞，或表达4-1BBL和膜结合白细胞介素-21（IL-21）的K562细胞。NK细胞扩增培养促使多样化克隆增殖；第14天收获时，细胞保留了起始条形码谱库的50%以上。以Shannon指数衡量的多样性在培养后仍得以维持。在LCL和K562两种饲养体系中，均观察到寿命较长、推测具有记忆样特征的NK细胞克隆增殖；这些克隆平均占扩增后细胞总体克隆谱的31%。这些实验揭示了扩增型NK细胞临床产品的克隆构成。
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Multiple clinical trials exploring the potential of adoptive natural killer (NK) cell therapy for cancer have employed ex vivo expansion using feeder cells to obtain large numbers of NK cells.
We have previously utilized the rhesus macaque model to clonally track the NK cell progeny of barcode-transduced CD34 + stem and progenitor cells after transplant. In this study, NK cells from barcoded rhesus macaques were used to study the changes in NK cell clonal patterns that occurred during ex vivo expansion using culture protocols similar to those employed in clinical preparation of human NK cells including irradiated lymphoblastoid cell line (LCL) feeder cells or K562 cells expressing 4-1BBL and membrane-bound interleukin-21 (IL-21).
NK expansion cultures resulted in the proliferation of clonally diverse NK cells, which, at day 14 harvest, contained greater than 50% of the starting barcode repertoire. Diversity as measured by Shannon index was maintained after culture. With both LCL and K562 feeders, proliferation of long-lived putative memory-like NK cell clones was observed, with these clones continuing to constitute a mean of 31% of the total repertoire of expanded cells. These experiments provide insight into the clonal makeup of expanded NK cell clinical products.
论文信息
- 作者
- Allan DSJ、Wu C、Mortlock RD、Chakraborty M、Rezvani K、Davidson-Moncada JK、Dunbar CE、Childs RW
- 单位
- Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.United States
- 期刊
- Molecular therapy oncolytics2023 Mar 16
- 原文标识
- PubMed 36699615 · DOI 10.1016/j.omto.2022.12.006
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