肿瘤细胞治疗研究
英文原题：Dual CAR-NK cells targeting PD-L1 and ErbB2 (HER2) exhibit cooperative CAR signaling and counteract solid tumor heterogeneity.
同时靶向 PD-L1 与 ErbB2 可通过对抗原异质性提供抵抗力并经协同激活放大抗肿瘤信号，增强 CAR-NK 细胞对难治性实体瘤的疗效。
背景：嵌合抗原受体（CAR）工程化自然杀伤（NK）细胞对血液系统恶性肿瘤显示出强效疗效。相反，实体瘤因抗原表达异质性和免疫抑制性肿瘤微环境而难治；后者促进免疫逃逸，且很大程度上由检查点介导的抑制驱动。 方法：为克服这些障碍，研究者构建了新型双 CAR-NK 细胞，同时靶向免疫检查点 PD-L1 和肿瘤相关抗原 ErbB2（HER2）。通过慢病毒转导临床适用的 NK-92 细胞，使其表达 PD-L1.CAR 和 ErbB2.CAR。研究采用全面体外和体内实验，在多种实体瘤模型中评估抗肿瘤活性。 结果：双 CAR-NK 细胞对表达其中一种或两种靶点的乳腺癌、胰腺癌、胃癌和肺癌细胞系均表现出强效且选择性的细胞毒作用。在三维球体培养物和患者来源原发性卵巢癌细胞中也观察到相当疗效。值得注意的是，当一种抗原缺失或被阻断时，双 CAR-NK 仍保持强细胞毒性，可模拟抗原丢失介导的免疫逃逸；单 CAR-NK 不具备这一特征。机制上，每个 CAR 均可依赖相应抗原独立激活 MEK/ERK 通路；双 CAR 同时刺激则以协同方式增强信号应答。此外，NK 细胞遇到耐药癌细胞后产生的 IFN-γ 足以诱导 PD-L1 上调，从而进一步增强双 CAR 系统效力。在 PD-L1/ErbB2 双阳性乳腺癌异种移植模型中，双 CAR-NK 持续优于单靶点对照。 结论：同时靶向 PD-L1 和 ErbB2，可通过增强对抗原异质性的适应能力及协同放大抗肿瘤信号，提高 CAR-NK 对难治性实体瘤的疗效。该方法是一个有希望且可调整的实体瘤免疫治疗临床转化平台。
BACKGROUND: Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have shown potent efficacy against hematologic malignancies. In contrast, solid tumors remain difficult to treat due to heterogeneous antigen expression and an immunosuppressive tumor microenvironment that fosters immune evasion and is driven to a large part by checkpoint-mediated inhibition. METHODS: To overcome these barriers, we engineered novel dual CAR-NK cells targeting the immune checkpoint PD-L1 and the tumor-associated antigen ErbB2 (HER2). The clinically applicable NK-92 cell line was lentivirally transduced with PD-L1.CAR and ErbB2.CAR constructs. Antitumor activity was assessed across diverse solid tumor models using a comprehensive panel of in vitro and in vivo assays. RESULTS: Dual CAR-NK cells exhibited potent and selective cytotoxicity against breast, pancreatic, gastric, and lung cancer cell lines expressing either one or both targets. Comparable efficacy was observed in 3D spheroid cultures and against patient-derived primary ovarian cancer cells. Notably, dual CAR-NK cells retained strong cytotoxicity when one antigen was absent or blocked, modeling immune escape through antigen loss - a feature absent in single CAR-NK cells. Mechanistically, each CAR independently activated the MEK/ERK pathway in an antigen-dependent manner, while dual CAR stimulation potentiated the signaling response in a cooperative manner. Furthermore, IFN- produced by NK cells upon encounter of resistant cancer cells was sufficient to induce PD-L1 upregulation, thereby enhancing the potency of the dual CAR system. In a PD-L1/ErbB2 double-positive breast cancer xenograft model, dual CAR-NK cells consistently outperformed single-target controls. CONCLUSIONS: Dual targeting of PD-L1 and ErbB2 enhances CAR-NK cell efficacy against refractory solid tumors by providing resilience to antigen heterogeneity and amplifying antitumor signaling through cooperative activation. This approach represents a promising and adaptable platform for clinical translation in solid tumor immunotherapy.
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