肿瘤细胞治疗研究
英文原题：Exploring Glypican-3 targeted CAR-NK treatment and potential therapy resistance in hepatocellular carcinoma.
肝细胞癌（HCC）是原发性肝癌中最常见的类型，也是全球癌症相关死亡的第二大原因。
肝细胞癌（HCC）是原发性肝癌最常见的类型，也是全球癌症相关死亡的第二大原因。尽管当前HCC治疗取得了进展，但它仍然是一种预后不良的恶性肿瘤。因此，迫切需要为HCC患者开发新的治疗选择。嵌合抗原受体（CAR）修饰的自然杀伤（NK）细胞已显示出强大的抗肿瘤作用，使其成为癌症治疗中一种有前景的免疫治疗策略。磷脂酰肌醇蛋白聚糖-3（GPC3）是一种细胞表面癌胚糖蛋白，在大多数HCC组织中高表达，但在正常组织中不表达，并作为癌变的关键驱动因素发挥作用。鉴于其在细胞表面的高表达水平，GPC3被认为是HCC一个有吸引力的免疫治疗靶点。在本研究中，利用NK92MI细胞（一种修饰的IL-2非依赖性NK细胞系）建立了两种GPC3特异性CAR-NK细胞，NK92MI/HN3和NK92MI/HS20。这些细胞系被工程化改造为表达第三代GPC3特异性CAR，随后评估了它们在HCC治疗中的活性。我们发现，NK92MI/HN3细胞而非NK92MI/HS20细胞在体外对GPC3+ HepG2细胞表现出显著的细胞毒性作用，并在使用NSG小鼠的异种移植模型中有效抑制了肿瘤生长。此外，经辐照的NK92MI/HN3细胞显示出与未经辐照的NK92MI/HN3细胞相似的抗肿瘤疗效。进一步地，我们观察到NK92MI/HN3细胞对GPC3异构体2过表达细胞系（Sk-Hep1-v2）的杀伤活性高于对GPC3异构体1过表达细胞系（Sk-Hep1-v1）的杀伤活性。这表明HCC中不同GPC3亚型的存在可能影响NK92MI/HN3细胞的细胞毒性活性，并可能影响治疗结果。这些发现凸显了NK92MI/HN3细胞有效的抗HCC作用，并揭示了GPC3亚型在影响治疗结果中的作用，提示应考虑进行亚型分析以优化CAR-NK疗法，从而改善患者预后。
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and the second leading cause of cancer-related mortality globally. Despite advancements in current HCC treatment, it remains a malignancy with poor prognosis. Therefore, developing novel treatment options for patients with HCC is urgently needed. Chimeric antigen receptor (CAR)-modified natural killer (NK) cells have demonstrated potent anti-tumor effects, making them as a promising immunotherapy strategy for cancer treatment. Glypican-3 (GPC3), a cell surface oncofetal glycoprotein, is highly expressed in most HCC tissues, but not in normal tissues, and functions as a key driver of carcinogenesis. Given its high expression level on the cell surface, GPC3 is considered as an attractive immunotherapy target for HCC. In this study, two GPC3-specific CAR-NK cells, NK92MI/HN3 and NK92MI/HS20, were established using NK92MI cells, a modified IL-2-independent NK cell line. These cell lines were engineered with third generation GPC3-specific CARs, and their activities were subsequently evaluated in the treatment of HCC. We found that NK92MI/HN3 cells, rather than NK92MI/HS20 cells, exhibited a significant cytotoxicity effect against GPC3+ HepG2 cells in vitro and efficiently suppressed tumor growth in a xenograft model using NSG mice. In addition, irradiated NK92MI/HN3 cells displayed similar anti-tumor efficacy to unirradiated NK92MI/HN3 cells. Furthermore, we observed that NK92MI/HN3 cells showed higher killing activity against the GPC3 isoform 2 overexpression cell line (Sk-Hep1-v2) than those with GPC3 isoform 1 overexpression cell line (Sk-Hep1-v1). This suggest that the presence of different GPC3 isoforms in HCC may impact the cytotoxicity activity of NK92MI/HN3 cells and potentially influence therapeutic outcomes. These findings highlight the effective anti-HCC effects of NK92MI/HN3 cells and reveal the role of GPC3 isoforms in influencing therapy outcomes, suggesting that isoform analysis should be considered to optimize CAR-NK therapies to improve patient outcomes.
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