Liver-infiltrating CD11b-CD27- NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression.

Natural killer (NK) cells have a vital role in killing hepatocellular carcinoma (HCC) cells; however, the mechanism underlying tumor-infiltrating NK (TINK)-cell dysfunction remains poorly understood. Using flow cytometry staining, we precisely characterized the frequency, phenotype and function of NK subsets distinguished by CD27 and CD11b in 30 patients with HCC in comparison to 30 healthy controls. Interestingly, we found a substantial proportion of liver-infiltrating CD11b-CD27- (DN) NK subsets in tumor tissue from HCC patients. Remarkably, these relatively expanded DN NK subsets exhibited an inactive and immature phenotype. By detecting the expression of CD107a and interferon-gamma (IFN-γ) on NK subsets and NK cells, we demonstrated that DN NK subsets exhibited a poor cytotoxic capacity and deficient potential to produce IFN-γ in comparison to the other three subsets, which contributed to the dysfunction of TINK cells in HCC patients. In addition, we found that the presence of DN NK cells was closely associated with the clinical outcomes of HCC patients, as the frequency of DN NK cells among TINK cells was positively correlated with tumor stage and size. A large percentage of DN NK cells among TINK cells was an independent prognostic factor for lower survival in the 60-month follow-up period. In conclusion, a substantial proportion of CD11b-CD27-NK subsets among TINK cells accounts for NK-cell dysfunction in patients with HCC and is associated with tumor progression. Our study may provide a novel therapeutic target for the treatment of patients with HCC.

Altered Immune Profiles of Natural Killer Cells in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Natural killer (NK) cells are the main effective component of the innate immune system that responds to chronic hepatitis B (CHB) infection. Although numerous studies have reported the immune profiles of NK cells in CHB patients, they are limited by inconsistent results. Thus, we performed a meta-analysis to characterize reliably the immune profiles of NK cells after CHB infection, specifically frequency, phenotype, and function. METHODS: A literature search of the computer databases MEDLINE, PUBMED, EMBASE, and Cochrane Center Register of Controlled Trails was performed and 19 studies were selected. The standard mean difference (SMD) and 95% confidence interval (CI) of each continuous variable was estimated with a fixed effects model when I2 < 50% for the test for heterogeneity, or the random effects model otherwise. Publication bias was evaluated using Begg's and Egger's tests. RESULTS: The meta-analysis of publications that reported frequency of peripheral NK cells showed that NK cell levels in CHB patients were significantly lower compared with that of healthy controls. A higher frequency of CD56bright NK subsets was found in CHB patients, but the CD56dim NK subsets of CHB patients and healthy controls were similar. CHB patients before and after antiviral therapy with nucleotide analogues (NUCs) showed no statistical difference in NK frequency. The activating receptors were upregulated, whereas inhibitory receptors were comparable in the peripheral NK cells of CHB individuals and healthy controls. NK cells of CHB patients displayed higher cytotoxic potency as evidenced by CD107a protein levels and conserved potency to produce interferon-gamma (IFNγ), compared with their healthy counterparts. CONCLUSION: Our results revealed that CHB patients had a lower frequency of NK cells compared with healthy individuals not treatable with antiviral NUC therapy. With an activating phenotype, NK cells in CHB patients showed better cytotoxic potency and conserved IFNγ production.