In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma patient-derived xenografts (HCC-PDX) encounter limitations in NK cell infiltration, hindering studies on NK cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 reinstated persistent NK cell reconstitution and infiltration in HCC-PDX in humanized mice. scRNA-seq revealed NK cell and T cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights.

中文翻译：

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单细胞 RNA 测序通过 PD-1 和 TIGIT 共靶向揭示 CD56+ NK 细胞和 CD8+ T 细胞在人源化小鼠中的抗肿瘤效力


在实体瘤中，免疫抑制性肿瘤微环境中自然杀伤 （NK） 细胞和细胞毒性 T 细胞的耗竭对有效控制肿瘤构成了挑战。肝细胞癌患者来源的异种移植物 （HCC-PDX） 的常规人源化小鼠模型在 NK 细胞浸润方面遇到局限性，阻碍了 NK 细胞免疫生物学的研究。在这里，我们介绍了一种改进的人源化小鼠模型，该模型在 HCC-PDX 中恢复了 NK 细胞的重建和浸润，并结合单细胞 RNA 测序 （scRNA-seq） 来确定潜在的抗 HCC 治疗方法。携带人白细胞介素 15 的腺相关病毒的单次给药恢复了人源化小鼠 HCC-PDX 中持续的 NK 细胞重建和浸润。scRNA-seq 显示 PDCD1 和 TIGIT 水平升高的 NK 细胞和 T 细胞亚群。值得注意的是，抗 PD-1 和抗 TIGIT 抗体的联合治疗减轻了人源化小鼠的 HCC 负担，证明了 NK 细胞依赖性疗效。大量 RNA 测序分析还揭示了肿瘤转录组的显着改变，这可能导致联合治疗后进一步耐药，值得进一步研究。作为一种新兴策略，正在进行的抗 PD-1 和抗 TIGIT 抗体临床试验提供的数据有限。改进的人源化小鼠 HCC-PDX 模型不仅阐明了 NK 细胞的关键作用，而且还为评估联合疗法和其他潜在方案的安全性和抗肿瘤疗效提供了强大的平台，补充了临床见解。