肿瘤细胞治疗研究
英文原题：Soluble programmed death ligand-1-induced immunosuppressive effects on chimeric antigen receptor-natural killer cells targeting Glypican-3 in hepatocellular carcinoma.
尽管嵌合抗原受体（CAR）-自然杀伤（NK）细胞的临床前研究对多种肿瘤有效，但肿瘤微环境介导的免疫抑制阻碍了其应用，并且已经探索了多种努力提高其对抗实体瘤的效果。
尽管临床前研究显示嵌合抗原受体（CAR）自然杀伤（NK）细胞对多种肿瘤有效，肿瘤微环境介导的免疫抑制仍妨碍其应用。研究者已探索多种方法增强其对抗实体瘤的效果。Glypican 3（GPC3）是肝细胞癌（HCC）的有前景靶点，靶向 GPC3 的 CAR-T 已进入临床试验。本研究基于靶向 GPC3 的亲和力增强抗体 hYP7，构建 GPC3-CAR-NK 细胞，探索其治疗 HCC 的潜在功能。研究发现，HCC 患者分泌高水平可溶性程序性死亡配体 1（sPD-L1），会抑制靶向 GPC3 的 CAR-NK 细胞功能。此外，研究者将高亲和力 sPD-L1 变体 L3C7c-Fc 与 GPC3-CAR-NK 联用，以解决 GPC3-CAR-NK 受抑制的问题。结果显示，L3C7c-Fc 可逆转 sPD-L1 的抑制作用，增强 CAR-NK 疗效，为后续开发 HCC 免疫治疗策略提供实验依据。
Although the pre-clinical study of chimeric antigen receptor (CAR)-natural killer (NK) cell was effective against various tumours, immunosuppression mediated by tumour microenvironment hampers their application and several efforts have been explored to improve their effect in combating solid tumours. Glypican 3 (GPC3) is a promising target for hepatocellular carcinoma (HCC), and CAR-T cells targeting GPC3 have been tested in clinical trials. Based on an affinity-enhanced antibody (hYP7) targeting GPC3, we constructed GPC3-CAR-NK cells to explore their potential function in the treatment of HCC. We found that patients with HCC secreted high levels of soluble programmed death-ligand 1 (sPD-L1), which inhibits the function of CAR-NK cells targeting GPC3. In addition, we combined high-affinity sPD-L1 variant (L3C7c-Fc) with GPC3-CAR-NK cells to solve the problem of GPC3-CAR-NK inhibition. Our studies demonstrated that L3C7c-Fc could enhance the therapeutic effect of CAR-NK cells by reversing the suppression of sPD-L1, which provides the experimental evidence for the subsequent development of HCC immunotherapy strategies.
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