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

Abstract

BackgroundNatural 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.MethodsSeveral 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).Results26 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.ConclusionNK 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.

Natural killer group 2D‐major histocompatibility complex class I polypeptide‐related sequence A activation enhances natural killer cell‐mediated immunity against hepatocellular carcinoma: A review

“…A meta-analysis showed that the percentage of infiltrating NK cells in HCC strongly correlates to a better patient outcome. 6 Furthermore, various in vitro and in vivo studies have identified NK cells and CD8 þ T lymphocytes as promising therapeutic targets in HCC. Among the various targets identified in previous studies, we focused on the NKG2D-MICA relationship based on our previous genome-wide association study data from chronic viral hepatitis, which demonstrated the critical role of MICA in hepatocarcinogenesis.…”

“…5 In addition, the percentage of infiltrating NK cells in HCC correlates with better patient outcomes. 6 Activation of members of the natural cytotoxicity receptor family, including NK group 2D (NKG2D), results in the release of preformed cytolytic granules containing granzyme B and perforin 3 . Furthermore, the relationship between membrane-bound NKG2D ligand (mNKG2DL) and its corresponding receptor, NKG2D, is essential for the effective elimination of HCC.…”

Baseline splenic volume as a biomarker for clinical outcome and circulating lymphocyte count in gastric cancer

“…A growing number of studies suggested that NK cells can be educated during development, possess antigen-specific receptors, undergo clonal expansion and acquire immunological memory ( 53 ). Although high circulating NK cell count was associated with better OS in gastric cancer ( 23 ), the prognostic role of NK cells was conflicted in various cancers and warrant further study ( 54 – 57 ).…”

Perspectives for novel therapeutic concepts in hepatocellular carcinoma targeting the stromal and innate immune microenvironment

“…124 In human HCC, high infiltration of NK cells has been shown to be associated with a favourable prognosis. 125,126 Moreover, NK cell frequencies in both peripheral blood and tumour tissue are decreased in patients with HCC. 127 In patients with HCC, a decrease in DC frequency was observed compared to healthy controls.…”