肿瘤细胞治疗研究
英文原题：Disruption of TGF-β signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells.
我们的发现表明，要实现 NK 细胞针对 HCC 的有效功能，阻断 TGF-β 信号是必需的，对其他高表达 TGF-β 的恶性肿瘤可能也是如此。
肝细胞癌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表达，可抑制免疫细胞活性。本研究利用人诱导多能干细胞生成NK细胞，并通过敲除TGF-β受体2或表达其显性负性形式，使细胞抵抗TGF-β抑制；同时构建靶向GPC3或AFP的CAR。两种改造均增强抗肝癌活性。单独在iPSC-NK上表达抗肝癌CAR并不足以产生有效作用，必须同时抑制TGF-β信号。结果表明，阻断TGF-β信号是NK细胞有效攻击肝癌及其他高表达TGF-β恶性肿瘤的重要条件。
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF- ) 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- receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF- 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- 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- activity. Our findings demonstrate that TGF- signaling blockade is required for effective NK cell function against HCC and potentially other malignancies that express high levels of TGF- .
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