The Clinical Significance And Function Of NK Cells In Chronic Lymphocytic Leukemia

Objective:Natural killer(NK)cells are essential components of the innate immune system and play a critical role in host immunity against cancer and virus-infected cells.The aim of our present study was to explore the distribution of absolute NK cell counts in peripheral blood in patients with chronic lymphocytic leukemia(CLL),evaluate correlation with other clinical indicators,the dynamic change of NK cell counts and relevant prognostic significance.Methods:A total of 273 previously untreated patients with CLL from April 2004 and October 2015 were enrolled into this retrospective study.We analysed the T cell subsets of all patients and figured out the number of NK cells.Comparisons of NK cell count as continuous parameter in different groups were described using Mann-Whitney U test and the Kruskal-Wallis test.Kaplan-Meier method was used to survival analysis,and the Cox proportional hazards models were used for the estimation of prognostic factors.Results:The median absolute NK cell counts were 0.63×109/L(range:0.01-5.83×109/L)in all the 273 CLL cases.The most discriminative cut-points of NK cell count at diagnosis was defined as 0.40×109/L by the use of X-tile.We divided the cohort of CLL into two groups based on the cut-off value and found that patients with lower NK cell counts(<0.40×109/L)had a significantly shorter OS than those with higher NK cell counts(?0.40×109/L),the 5-year OS was 63.7%and 79.2%respectively(P=0.0014).The higher level NK cell counts at diagnosis in patients was positively correlated with Binet stage A/B(P=0.031),ZAP70<20%(P<0.001),normal level of ALB(P=0.05)and ?2-MG(P=0.03).Multivariate analysis confirmed NK cell counts as an independent risk factor for OS(P=0.028).We observed the dynamic of NK cell counts of 19 patients during therapy and follow-up.Eight patients of therapy responders had a stable level of NK cell percentage after treatment(P=0.779).In contrast,6 subjects suffering from disease progression had a rapid decrease in NK cell proportion(P=0.004).NK cell counts refined the prognostication based on conventional CLL risk factors,which suggested that addition of NK cell counts to classical prognostic factors should improve the risk stratification in patients with CLL.Conclusion:Absolute NK cell counts in peripheral blood of CLL patients may reflect the condition of immune system,high number of NK cells indicates superior prognosis.The dynamic changes of NK cell counts during the course may reflect the disease state,and refined the prognostication based on conventional CLL risk factors.Absolute NK cell counts may be a potential independent survival factor for chronic lymphocytic leukemia.Objective:Natural killer(NK)cells,the prototypic member of innate lymphoid cells,are important effectors of anticancer immune response.NK cell activity is dependent on activating and inhibitory signals transmitted by a large repertoire of surface receptors.NKG2D(Natural killer group 2,member D)play a key role in NK cell activation.Previous in vitro study had proved that chidamide upregulates the expression of NKG2D,increasing the activity of NK cells.We stimulated CLL cells with chidamide in vitro to upregulate NKG2D expression and explore the clinical significance.Methods:Peripheral cells from 17 CLL patients were incubated in medium with different concentrations of chidamide.After 24h,48h-incubation,CLL cells were harvested to meansure NKG2D expression by multiparameter flow cytometry.Statistical analysis was performed by software SPSS(version.19.0 windows),Comparisons of NKG2D expression in different groups were described using Mann-Whitney U test.A P value of<0.05 was considered significant.Results:Seventeen CLL patients consisted of 13 males and 4 females,whose medium age was 64(35-75)years old.According to the Binet clinical staging system,4 patients were in Binet A stage with 4 in stage B and 9 in stage C.Seven patients had CLL cells that expressed mutated IGHV gene.Mutation of p53 gene was present in 2 patients,while 4 patients had absence of p53 gene.The expression of NKG2D receptor in CLL patients was significantly lower than the healthy controls(MFI:280.4±20.60 vs,399.1±22.88,P=0.003;Percentage:2.33±1.75 vs.4.16± 1.74,P=0.013).The findings indicated that chidamide upregulated NKG2D express in time-and concentration-dependent manners.What's more,the upregulation of NKG2D have no correlation with gender,age,Binet stage,IGHV mutation and p53 disruption(All P>0.05).Conclusion:Our study has revealed that the expression of NKG2D receptor in CLL patients was significantly lower than healthy controls.Chidamide could upregulate the expression of NKG2D receptor that signicantly impact NK cell activity.