Disruption of TGF-β signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-07-09 DOI:10.1016/j.stem.2024.06.009
Jaya Lakshmi Thangaraj, Michael Coffey, Edith Lopez, Dan S. Kaufman
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Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF-β) is highly expressed in the liver tumor microenvironment and is known to inhibit immune cell activity. Here, we used human induced pluripotent stem cells (iPSCs) to produce natural killer (NK) cells engineered to mediate improved anti-HCC activity. Specifically, we produced iPSC-NK cells with either knockout TGF-β receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-β receptor 2 (TGFBR2-DN) combined with chimeric antigen receptors (CARs) that target either GPC3 or AFP. The TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-β inhibition and improved anti-HCC activity. However, expression of anti-HCC CARs on iPSC-NK cells did not lead to effective anti-HCC activity unless there was also inhibition of TGF-β activity. Our findings demonstrate that TGF-β signaling blockade is required for effective NK cell function against HCC and potentially other malignancies that express high levels of TGF-β.

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人 iPSC 衍生 NK 细胞有效杀伤肝细胞癌需要 TGF-β 信号通路的干扰
肝细胞癌(HCC)是最常见的原发性肝癌。转化生长因子β(TGF-β)在肝脏肿瘤微环境中高度表达,已知会抑制免疫细胞的活性。在这里,我们利用人体诱导多能干细胞(iPSCs)来培育天然杀伤(NK)细胞,以改善其抗肝癌活性。具体来说,我们制备了敲除 TGF-β 受体 2(TGFBR2-KO)或表达显性阴性(DN)形式 TGF-β 受体 2(TGFBR2-DN)的 iPSC-NK 细胞,这些细胞与靶向 GPC3 或 AFP 的嵌合抗原受体(CAR)相结合。TGFBR2-KO和TGFBR2-DN iPSC-NK细胞对TGF-β抑制具有抗性,并提高了抗HCC活性。然而,在 iPSC-NK 细胞上表达抗HCC CARs 并不能带来有效的抗HCC 活性,除非同时抑制 TGF-β 活性。我们的研究结果表明,阻断 TGF-β 信号转导是 NK 细胞有效对抗 HCC 以及其他可能表达高水平 TGF-β 的恶性肿瘤的必要条件。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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