Department of Hepatobiliary Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China; Department of Infectious Diseases, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.
Int Immunopharmacol. 2019 May;70:1-8. doi: 10.1016/j.intimp.2019.02.007. Epub 2019 Feb 16.
Hepatocellular carcinoma (HCC) is the most common liver malignancy with dismal prognosis and limited treatment options. Natural killer (NK) cells are critical components of antitumor immunity due to their capacity to eliminate MHC class I-deficient cells. To evaluate the function of NK cells in HCC patients, circulating CD3CD56 NK cells were collected from HBV-associated HCC patients and healthy control individuals. Compared to NK cells from healthy controls, NK cells from HCC patients presented functional impairment, characterized by significantly reduced cytotoxicity, degranulation, and cytokine production. Exogenous IL-21 could reinvigorate NK cells from HCC patients, resulting in significantly increased levels of cytotoxicity, degranulation, and cytokine expression. However, IL-21-treated NK cells from HCC patients still presented lower response than IL-21-treated NK cells from healthy controls. IL-21 resulted in increased phosphorylation of both STAT1 and STAT3 in NK cells. Inhibition of STAT1, but not STAT3, significantly reduced IL-21-mediated reinvigoration of NK function. Together, this study demonstrated that NK cells in HBV-associated HCC patients presented functional impairments that could be reverted by IL-21 in a STAT1-mediated mechanism.
肝细胞癌 (HCC) 是最常见的肝脏恶性肿瘤，预后不良，治疗选择有限。自然杀伤 (NK) 细胞因其能够消除 MHC Ⅰ类缺陷细胞的能力，是抗肿瘤免疫的关键组成部分。为了评估 NK 细胞在 HCC 患者中的功能，从 HBV 相关 HCC 患者和健康对照个体中收集循环 CD3CD56 NK 细胞。与来自健康对照的 NK 细胞相比，HCC 患者的 NK 细胞表现出功能障碍，其特征是细胞毒性、脱颗粒和细胞因子产生显著降低。外源性 IL-21 可以重振 HCC 患者的 NK 细胞，导致细胞毒性、脱颗粒和细胞因子表达显著增加。然而，IL-21 处理的 HCC 患者的 NK 细胞的反应仍低于 IL-21 处理的健康对照的 NK 细胞。IL-21 导致 NK 细胞中 STAT1 和 STAT3 的磷酸化均增加。STAT1 的抑制，但不是 STAT3 的抑制，显著降低了 IL-21 介导的 NK 功能的重振。总之，这项研究表明，HBV 相关 HCC 患者的 NK 细胞表现出功能障碍，可以通过 STAT1 介导的机制被 IL-21 逆转。
