肿瘤细胞治疗研究
英文原题：Enhanced PD-L1 targeting boosts the cytotoxic activity of FOLR1- CAR NK92 cells against ovarian cancer.
Enhanced PD-L1 targeting boosts the cytotoxic activity of FOLR1- CAR NK92 cells against ovarian cancer.
本研究开发的串联双特异性 CAR-NK92 细胞代表了免疫治疗领域的一项有意义进展。
嵌合抗原受体（CAR）T细胞已在血液系统恶性肿瘤中取得显著成功，但其应用伴有细胞因子释放综合征（CRS）和神经毒性等风险。相比之下，CAR-NK细胞不仅可避免这些毒性，还保留NK细胞天然细胞毒活性，在癌症免疫治疗中展现出巨大潜力。我们此前研究显示，叶酸受体α（FOLR1）靶向CAR-NK92细胞对卵巢癌（OC）疗效强劲。然而，CAR-NK治疗包括OC在内的实体瘤仍面临肿瘤抗原异质性和免疫抑制性肿瘤微环境（ITME）等挑战。ITME的重要介质之一是程序性死亡配体1（PD-L1），其不仅与OC预后不良相关，还通过PD-1/PD-L1轴驱动T细胞耗竭。此外，NK细胞疗法可诱导PD-L1表达上调，使其成为OC可行的治疗靶点。为增强CAR技术治疗OC的潜力，我们基于既有FOLR1-CAR设计，构建两种新型第三代双特异性CAR-NK92细胞：串联PD-L1/FOLR1-CAR（Tan-CAR1）NK92和串联FOLR1/PD-L1-CAR（Tan-CAR2）NK92，旨在同时靶向FOLR1和PD-L1。值得注意的是，我们确认效应细胞与靶细胞共培养上清中PD-L1表达显著上调。体外实验中，与FOLR1-CAR NK92相比，Tan-CAR2 NK92对FOLR1高表达、PD-L1低表达OC细胞的细胞毒性显著更强，脱颗粒也增强。在异种移植小鼠模型中，Tan-CAR2 NK92显示有效肿瘤浸润，诱导的肿瘤消退程度显著高于FOLR1-CAR NK92和PD-L1-CAR NK92组。总之，本研究开发的串联双特异性CAR-NK92细胞代表免疫治疗的一项重要进展。其双重机制——扩大抗原识别范围并增强免疫细胞浸润——有效应对OC治疗的两大障碍，为难治病例提供有前景策略。
Chimeric antigen receptor (CAR)-T cells have achieved remarkable success against hematologic malignancies; however, their application is associated with risks such as cytokine release syndrome (CRS) and neurotoxicity. In contrast, CAR-NK cells not only avoid these toxicities but also retain the natural cytotoxic activity of NK cells, demonstrating great potential for cancer immunotherapy.Our previous study demonstrated the potent efficacy of folate receptor alpha (FOLR1)-targeted CAR-NK92 cells against ovarian cancer (OC). Nevertheless, the application of CAR-NK therapy in solid tumors, including OC, still faces challenges such as tumor antigen heterogeneity and the immunosuppressive tumor microenvironment (ITME). A key mediator of ITME is programmed death-ligand 1 (PD-L1), which not only correlates with poor prognosis in OC but also drives T cell exhaustion via the PD-1/PD-L1 axis. Moreover, its inducible upregulation under NK cell-based therapy supports PD-L1 as a viable therapeutic target in OC.To enhance the therapeutic potential of CAR technology for OC, we engineered two novel third-generation bispecific CAR-NK92 cells based on our prior FOLR1-CAR design. These constructs-Tandem PD-L1/FOLR1-CAR (Tan-CAR1) NK92 and Tandem FOLR1/PD-L1-CAR (Tan-CAR2) NK92-were designed to simultaneously target FOLR1 and PD-L1. Notably, we confirmed that PD-L1 expression was significantly upregulated in the co-culture supernatant of effector and target cells. In vitro, Tan-CAR2 NK92 cells exhibited markedly superior cytotoxicity against FOLR1 high PD-L1 low OC cells and enhanced degranulation compared with FOLR1-CAR NK92 cells. In xenograft mouse models, Tan-CAR2 NK92 cells showed effective tumor infiltration and induced significantly greater tumor regression than both FOLR1-CAR NK92 and PD-L1-CAR NK92 groups. In conclusion, the tandem bispecific CAR-NK92 cells developed in this study represent a meaningful advance in immunotherapy. Their dual mechanism-broader antigen recognition and enhanced immune infiltration-effectively addresses two major therapeutic barriers in OC, offering a promising strategy for treating refractory cases.
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