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Meta-Analysis
. 2022 Apr 7:13:872353.
doi: 10.3389/fimmu.2022.872353. eCollection 2022.

The Prognostic Value of Natural Killer Cells and Their Receptors/Ligands in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Jun-Shuai Xue  1 , Zi-Niu Ding  1 , Guang-Xiao Meng  1 , Lun-Jie Yan  1 , Hui Liu  1 , Hai-Chao Li  1 , Sheng-Yu Yao  1 , Bao-Wen Tian  1 , Zhao-Ru Dong  1 , Zhi-Qiang Chen  1 , Jian-Guo Hong  1 , Dong-Xu Wang  1 , Tao Li  1   2
Affiliations
Meta-Analysis

The Prognostic Value of Natural Killer Cells and Their Receptors/Ligands in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Jun-Shuai Xue et al. Front Immunol. .

Abstract

Background: Natural killer (NK) cells play major roles in eliminating tumor cells. Preliminary studies have shown that NK cells and their receptors/ligands have prognostic value in malignant tumors. However, the relevance of NK cells and their receptors/ligands level to the prognosis of hepatocellular carcinoma (HCC) remains unclear.

Methods: Several electronic databases were searched from database inception to November 8, 2021. Random effects were introduced to this meta-analysis. The relevance of NK cells and their receptors/ligands level to the prognosis of HCC was evaluated using hazard ratios (HRs) with 95% confidence interval (95%CI).

Results: 26 studies were included in the analysis. The pooled results showed that high NK cells levels were associated with better overall survival (HR=0.70, 95%CI 0.57-0.86, P=0.001) and disease-free survival (HR=0.61, 95%CI 0.40-0.93, P=0.022) of HCC patients. In subgroup analysis for overall survival, CD57+ NK cells (HR=0.70, 95%CI 0.55-0.89, P=0.004) had better prognostic value over CD56+ NK cells (HR=0.69, 95%CI 0.38-1.25, P=0.224), and intratumor NK cells had better prognostic value (HR=0.71, 95%CI 0.55-0.90, P=0.005) over peripheral NK cells (HR=0.66, 95%CI 0.41-1.06, P=0.088). In addition, high level of NK cell inhibitory receptors predicted increased recurrence of HCC, while the prognostic role of NK cell activating receptors remained unclear.

Conclusion: NK cells and their inhibitory receptors have prognostic value for HCC. The prognostic role of NK cell activating receptors is unclear and more high-quality prospective studies are essential to evaluate the prognostic value of NK cells and their receptors/ligands for HCC.

Keywords: hepatocellular carcinoma; ligand; natural killer cells; prognosis; receptor.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study flow chart of the data extraction process and selection of studies for meta-analysis.
Figure 2
Figure 2
Forest plot of NK cells in HCC. (A) Forest plot of NK cells and OS in HCC. (B) Forest plot of NK cells and DFS/RFS/TTR/PFS in HCC. CI, Confidence interval; HR, Hazard ratio; HCC, Hepatocellular carcinoma; NK, Natural killer; OS, Overall survival; DFS, Disease-free survival; RFS, Recurrence-free survival; TTR, Time-to recurrence; PFS, Progression-free survival.
Figure 3
Figure 3
Funnel plots of NK cells in HCC. (A) Funnel plots of HR for OS of NK cells. (B) Funnel plots of HR for DFS/RFS/TTR/PFS of NK cells. CI, Confidence interval; HR, Hazard ratio; HCC, Hepatocellular carcinoma; NK, Natural killer; OS, Overall survival; DFS, Disease-free survival; RFS, Recurrence-free survival; TTR, Time-to recurrence; PFS, Progression-free survival.
Figure 4
Figure 4
Forest plot of NK cells activating receptors/ligands in HCC. (A) Forest plot of NK cells activating receptors/ligands and OS in HCC. (B) Forest plot of NK cells activating receptors/ligands and DFS/RFS/PFS in HCC. CI, Confidence interval; HR, Hazard ratio; HCC, Hepatocellular carcinoma; NK, Natural killer; OS, Overall survival; DFS, Disease-free survival; RFS, Recurrence-free survival; PFS, Progression-free survival.
Figure 5
Figure 5
Forest plot of NK cells inhibitory receptors/ligands in HCC. (A) Forest plot of NK cells inhibitory receptors/ligands and OS in HCC. (B) Forest plot of NK cells inhibitory receptors/ligands and DFS/PFS in HCC. CI, Confidence interval; HR, Hazard ratio; HCC, Hepatocellular carcinoma; NK, Natural killer; OS, Overall survival; DFS, Disease-free survival; PFS, Progression-free survival.
Figure 6
Figure 6
Sensitivity analysis of NK cells. (A) Sensitivity analysis for OS of NK cells. (B) Sensitivity analysis for DFS/RFS/TTR/PFS of NK cells. CI, Confidence interval; HR, Hazard ratio; NK, Natural killer; OS, Overall survival; DFS, Disease-free survival; RFS, Recurrence-free survival; TTR, Time-to recurrence; PFS, Progression-free survival.
Figure 7
Figure 7
Evaluation of publication bias of NK cells using Begg’s test and Egger’s test. (A) Begg’s test for OS of NK cells, P=0.732. (B) Egger’s test for OS of NK cells, P=0.564. (C) Begg’s test for DFS/RFS/TTR/PFS of NK cells, P=0.602. (D) Egger’s test for DFS/RFS/TTR/PFS of NK cells, P=0.401. lnhr, the ln of HR; s.e., standard error; NK, Natural killer; OS, Overall survival, DFS, Disease-free survival; RFS, Recurrence-free survival; TTR, Time-to recurrence; PFS, Progression-free survival.
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