美国加州大学Dan S. Kaufman团队近期取得重要工作进展，他们研究提出，TGF-β信号通路的破坏是介导人iPSC来源NK细胞有效杀伤肝细胞癌所必需的。相关研究成果2024年7月9日在线发表于《细胞—干细胞》杂志上。

据介绍，肝细胞癌(HCC)是最常见的原发性肝癌类型。转化生长因子β（TGF-β）在肝肿瘤微环境中高度表达，已知可抑制免疫细胞活性。

研究人员使用人诱导多能干细胞（iPSC）产生自然杀伤细胞（NK），以介导抗HCC活性的提高。研究人员构建了具有敲除TGF-β受体2（TGFBR2-KO）或表达显性阴性（DN）形式的TGF-β接收器2（TGFFR2-DN）与靶向GPC3或AFP的嵌合抗原受体（CAR）结合的iPSC NK细胞。TGFBR2-KO和TGFBR2-DN iPSC NK细胞对TGF-β的抑制具有抗性，并提高了抗HCC活性。然而，抗HCC CAR在iPSC NK细胞上的表达并不能导致有效的抗HCC活性，除非同时抑制TGF-β活性。

总之，这一研究结果表明，TGF-β信号传导阻断是NK细胞有效抵抗HCC和潜在的其他表达高水平TGF-β的恶性肿瘤所必需的。

附：英文原文

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

Author: Jaya Lakshmi Thangaraj, Michael Coffey, Edith Lopez, Dan S. Kaufman

Issue&Volume: 2024-07-09

Abstract: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforminggrowth factor beta (TGF-β) is highly expressed in the liver tumor microenvironmentand is known to inhibit immune cell activity. Here, we used human induced pluripotentstem cells (iPSCs) to produce natural killer (NK) cells engineered to mediate improvedanti-HCC activity. Specifically, we produced iPSC-NK cells with either knockout TGF-βreceptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-βreceptor 2 (TGFBR2-DN) combined with chimeric antigen receptors (CARs) that targeteither GPC3 or AFP. The TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-βinhibition and improved anti-HCC activity. However, expression of anti-HCC CARs oniPSC-NK cells did not lead to effective anti-HCC activity unless there was also inhibitionof TGF-β activity. Our findings demonstrate that TGF-β signaling blockade is requiredfor effective NK cell function against HCC and potentially other malignancies thatexpress high levels of TGF-β.

DOI: 10.1016/j.stem.2024.06.009

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00217-0