肿瘤细胞治疗研究
英文原题：CAR-NK cell therapy combined with checkpoint inhibition induces an NKT cell response in glioblastoma.
CAR-NK cell therapy combined with checkpoint inhibition induces an NKT cell response in glioblastoma.
该联合治疗逆转了免疫抑制性肿瘤微环境，T 细胞和 NKT 细胞浸润增加。
背景：胶质母细胞瘤是侵袭性最强的原发性脑肿瘤，现有疗法疗效有限，且肿瘤微环境具有显著免疫抑制性。由于 HER2 在脑内生理表达极低，局部靶向 HER2 的免疫疗法具有较高肿瘤特异性。既往研究显示，针对 HER2 的 CAR-NK 单药治疗中等大小 GL261/HER2 肿瘤有效。方法：针对晚期 GL261/HER2 肿瘤，局部注射 CAR-NK 细胞并联合全身抗 PD-1 免疫检查点阻断。监测肿瘤生长和生存，并通过多重免疫荧光、光谱流式细胞术和 RNA 测序深入表征微环境。结果：未治疗的 GL261/HER2 肿瘤具有局部免疫抑制和高 PD-L1 表达特征。联合使用 NK-92/5.28.z 与全身抗 PD-1 后，产生强效抗肿瘤应答并带来长期生存。多重免疫荧光和光谱流式细胞术显示，接受 CAR-NK 与抗 PD-1 联合治疗的小鼠 CD4⁺ T 细胞浸润增加。联合治疗组还特异性出现一群表达 NKT 细胞标志物的 T 细胞，并通过免疫荧光染色得到进一步证实。结论：联合治疗逆转了免疫抑制性肿瘤微环境，增加 T 细胞和 NKT 细胞浸润，使 CAR-NK 单药治疗难以控制的晚期原位肿瘤获得有效治疗。
BACKGROUND: Glioblastoma is the most aggressive primary brain tumor with limited efficacy of established therapies, and a pronounced immunosuppressive tumor microenvironment. Targeting HER2 with local immunotherapy allows for high tumor specificity in the brain with physiologically very low expression. Monotherapy with CAR-NK cells targeted against HER2 has previously shown efficacy in medium-sized GL261/HER2 tumors. METHODS: Advanced GL261/HER2 tumors were treated by local CAR-NK cell injection combined with systemic anti-PD-1 checkpoint blockade. Tumor growth and survival were monitored. In-depth characterization of the microenvironment was performed by multiplex immune fluorescence, spectral flow cytometry and RNAseq. RESULTS: Untreated GL261/HER2 tumors were characterized by local immunosuppression and high PD-L1 expression. Combined treatment with NK-92/5.28.z and systemic anti-PD-1 induced robust anti-tumor response and long-term survival. Multiplex immunofluorescence and spectral flow cytometry showed increased CD4 + T cell infiltration in mice treated with CAR-NK cell and anti-PD-1 combination therapy. A cluster of T cells specifically emerging in the combination therapy group expressed markers of NKT cells, which was further verified by immunofluorescence staining. CONCLUSION: The combination therapy reverted the immunosuppressive tumor microenvironment with increased T and NKT cell infiltration. This resulted in successful treatment of advanced orthotopic tumors refractory to CAR-NK cell monotherapy.
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