PD-1 blockade improves the anti-tumor potency of exhausted CD3(+)CD56(+) NKT-like cells in patients with primary hepatocellular carcinoma.
PD-1 blockade improves the anti-tumor potency of exhausted CD3(+)CD56(+) NKT-like cells in patients with primary hepatocellular carcinoma.
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PD-1阻断可提高原发性肝细胞癌患者耗尽的CD3( )CD56( ) NKT样细胞的抗肿瘤效力
DOI：
10.1080/2162402x.2021.2002068
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发表时间：
2021
期刊：
影响因子：
7.2
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Tao L;Wang S;Kang G;Jiang S;Yin W;Zong L;Li J;Wang X
CD 3 + CD 56 + NKT样细胞在抗肿瘤免疫防御反应中起着关键作用。然而，关于原发性肝细胞癌（HCC）患者的循环NKT样细胞知之甚少。在本研究中，我们证明了HCC患者中循环NKT样细胞功能受损，抗PD-1阻断剂可提高其抗肿瘤效力。循环NKT细胞主要由CD 8 + T细胞组成。与健康供体相比，HCC患者之间循环NKT样细胞的频率和绝对计数相当。HCC患者的NKT样细胞产生TNF-α和IFN-γ的能力以及细胞毒活性受损。HCC患者NKT样细胞上活化受体NKG 2D的水平显著降低。与此相反，抑制性受体PD-1，Tim-3和CTLA-4的表达显着增加NKT样细胞在肝癌患者。同时，HCC患者的NKT样细胞上PD-L1的表达也上调。具体而言，与PD-1− NKT样细胞相比，PD-1+ NKT样细胞表达的NKG 2D水平较低，Tim-3和CTLA-4水平较高，IFN-γ水平较低。重要的是，用抗PD-1抗体阻断的PD-1有效地改善了来自HCC患者或健康供体的NKT样细胞的效应子功能。我们的研究结果揭示了HCC患者中NKT样细胞的功能特征，并提供了改善其功能的潜在靶点，这可能有利于HCC免疫治疗的优化。
ABSTRACT CD3+CD56+ NKT-like cells play pivotal roles in the anti-tumor immune defense response. However, little is known regarding circulating NKT-like cells in patients with primary hepatocellular carcinoma (HCC). In the present study, we demonstrate that circulating NKT-like cells in HCC patients are functionally impaired and anti-PD-1 blockade improves their anti-tumor potency. Circulating NKT cells were mainly comprised of CD8+ T cells. The frequencies and absolute counts of circulating NKT-like cells were comparable between HCC patents compared to healthy donors. NKT-like cells in HCC patients were impaired in their production of TNF-α and IFN-γ as well as cytotoxicity. The level of activating receptor NKG2D was significantly decreased on NKT-like cells in HCC patients. In contrast, the expression of inhibitory receptors PD-1, Tim-3, and CTLA-4 were markedly increased on NKT-like cells in HCC patients. Meanwhile, the expression of PD-L1 was also upregulated on NKT-like cells in HCC patients. In detail, PD-1+ NKT-like cells expressed lower levels of NKG2D, higher levels of Tim-3, and CTLA-4, and less IFN-γ when compared with PD-1− NKT-like cells. Importantly, PD-1 blocked with anti-PD-1 antibody effectively improved the effector function of NKT-like cells from HCC patients or healthy donors. Our findings unveil the functional characterization of NKT-like cells in HCC patients and provide the potential targets to improve their function, which might benefit the optimization of HCC immunotherapy.