肿瘤细胞治疗研究
英文原题：NR4A1 mediates NK-cell dysfunction in hepatocellular carcinoma via the IFN-γ/p-STAT1/IRF1 pathway.
NR4A1 mediates NK-cell dysfunction in hepatocellular carcinoma via the IFN-γ/p-STAT1/IRF1 pathway.
肝细胞癌（HCC）是全球范围内最致命的肿瘤之一，复发率高。
肝细胞癌（HCC）是全球范围内最致命的肿瘤之一，且复发率高。然而，HCC 的发生机制仍部分未被探索，而 HCC 治疗的效果仍然有限。本研究分析了核受体亚家族 4 A 组成员 1（NR4A1）在来源于 HCC 患者和荷瘤小鼠模型的肿瘤浸润自然杀伤（NK）细胞中的表达，以及 NR4A1 高表达和 NR4A1 低表达 NK 细胞的特征。此外，应用 CRISPR/Cas9 敲除 NR4A1 和过继转移实验，以验证 NR4A1 在肿瘤浸润 NK 细胞和抗 PD-1 治疗中的功能。本研究发现，NR4A1 在肿瘤浸润 NK 细胞中显著高表达，其通过调控 IFN-/p-STAT1/IRF1 信号通路介导肿瘤浸润 NK 细胞的功能障碍。在 NK 细胞中敲除 NR4A1 不仅恢复了 NK 细胞的抗肿瘤功能，还增强了抗 PD-1 治疗的疗效。本研究结果提示 NR4A1 在 NK 细胞抗 HCC 免疫进程中具有调控作用，这可能为 HCC 的免疫治疗提供新方向。
Hepatocellular carcinoma (HCC) is one of the most fatal tumours worldwide and has a high recurrence rate. Nevertheless, the mechanism of HCC genesis remains partly unexplored, while the efficiency of HCC treatments remains limited. The present study analysed the expression of nuclear receptor subfamily 4 group A member 1 (NR4A1) in tumour-infiltrating natural killer (NK) cells derived from both human patients with HCC and tumour-bearing mouse models, as well as the features of NR4A1 high and NR4A1 low NK cells. In addition, knockout of NR4A1 by CRISPR/Cas9 and adoptive transfer experiments were applied to verify the function of NR4A1 in both tumour-infiltrating NK cells and anti-PD-1 therapy. The present study found that NR4A1 was significantly highly expressed in tumour-infiltrating NK cells, which mediated the dysfunction of tumour-infiltrating NK cells by regulating the IFN- /p-STAT1/IRF1 signalling pathway. Knockout of NR4A1 in NK cells not only restored the antitumour function of NK cells but also enhanced the efficacy of anti-PD-1 therapy. The present findings suggest a regulatory role of NR4A1 in the immune progress of NK cells against HCC, which may provide a new direction for immunotherapies of HCC.
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