Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments
Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments
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DOI：
10.1080/2162402x.2016.1154249
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Missale, Gabriele
中科院分区：
文献类型：
--
作者：
Cariani, Elisabetta;Pilli, Massimo;Missale, Gabriele
NK细胞的数量和功能与癌症进展有关。目前尚缺乏对肝细胞癌中NK细胞表型和功能特征的详细分析。NK细胞的功能是由遗传因素决定的激活和抑制受体以及与转化或感染细胞上的同源配体的结合来调节的。我们评估了接受根治性治疗的肝癌患者NK细胞的表型和功能特征与临床结果的关系。对70例接受切除或消融治疗的肝细胞癌患者、18例健康志愿者和12例肝炎后肝硬变患者(对照组)的NK细胞进行了表型分析。基于表达不同表型NK细胞标志物的细胞的频率的无监督聚类将肝细胞癌患者分成不同的队列，并对结果进行比较。比较不同总生存期(OS)和疾病复发时间(TTR)的队列中NK细胞细胞因子的产生和细胞毒作用。经多因素分析，年龄、Child-Pugh分级和NK细胞表型聚类可独立识别OS差异显著的患者。预后较好的患者的NK细胞表达较高水平的细胞毒颗粒和CD3Zeta，较低水平的天然细胞毒性受体(NCR)与已知的负调节NCR功能的抑制性受体NKG2A共表达。与对照组相比，预后较差的患者组的细胞毒功能和干扰素-γ的产生显著降低(p<；0.05)。我们的结果显示NK细胞在控制肝癌进展和生存中的作用，为发展免疫治疗策略以增强NK细胞反应提供了基础。
NK-cell number and function have been associated with cancer progression. A detailed analysis of phenotypic and functional characteristics of NK-cells in HCC is still lacking. NK-cell function is regulated by activating and inhibitory receptors determined by genetic factors and engagement with cognate ligands on transformed or infected cells. We evaluated phenotypic and functional characteristic of NK-cells in HCC patients undergoing curative treatment in relation to clinical outcome. NK-cells from 70 HCC patients undergoing resection or ablative treatment, 18 healthy volunteers and 12 cirrhotic patients with HCV-infection (controls) were phenotypically characterized. Unsupervised clustering based on the frequency of cells expressing different phenotypic NK-cell markers segregated HCC patients into different cohorts that were compared for outcome. NK-cell cytokine production and cytotoxicity were compared between cohorts with different overall survival (OS) and time to disease recurrence (TTR). By multivariate analysis, age, Child-Pugh class and NK-cell phenotypic clustering could independently identify patients with significantly different OS. NK-cells from patients with better outcome expressed higher levels of cytotoxic granules and CD3 zeta and lower levels of natural cytotoxic receptors (NCRs) that were co-expressed with the inhibitory receptor NKG2A known to negatively regulate NCR function. Cytotoxic function and IFN gamma production were significantly lower in the cohort of patients with worse outcome compared to controls (p < 0.05). Our results show a role for NK-cells in the control of HCC progression and survival providing the basis for the development of immunotherapeutic strategies to potentiate NK-cell response.