Association Of Pretreatment Peripheral Blood Immune Parameters With Prognosis Of Patients With Hepatocellular Carcinoma After Microwave Ablation

Backgroud: Hepatocellular carcinoma (HCC) is the third leading cause of cancermortality worldwide, while in China HCC is the second leading cause of cancermortality. Because of the rich blood supply of HCC, tumor cell could spread to jacentand distant organs through blood. How to predict and detect the early recurrence andmetastasis is hot issue in the research field of HCC.Nonresolving Inflammation contributes significantly to the initiation andprogression of many kinds of malignant tumor. Inflammation microenvironment isconsidered the major battlefield between tumor promotion and antitumor immunity.In normal condition, immunosurveillance of human immune system could recognizeand remove the cells with malignant transformation, however, the role ofimmunosurveillance is limited, and the inhibitory cytokines secreted by tumor tissueand the inhibitory immune cells could suppress the anti-tumor immunity and promotethe development of tumor.Most of the HCC patients have a long disease history ofchronic viral hepatitis and liver cirrhosis. Due to the long-term chronic inflammation,most of the killer T cells were exhausted and the liver was in the condition ofimmunosuppression. Myeloid-derived suppressor cell and Tie2-expressing monocytesin peripheral blood as well as numerous inflammatory cytokines in serum couldinflect the immune state of HCC patients and have the potential values as anoninvasive markers in the diagnosis and detection of HCC recurrence.Evaluation ofimmune status has important clinical significance for the HCC patients beforemicrowave ablation.Methods: In the first part, from September2012to December201385HCC patientswho underwent TACE or microwave ablation in our hospital were recruited in our research prospectively. Before treatment according to the progression of HCC, thepatients were distributed into2groups and the healthy control group was setmeanwhille. Flow cytometry was used to detect the percentages of MDSC and TEMsin peripheral blood. Cytometric Bead Array was applied to measure the levels ofserum inflammatory cytokines. Statistical analyses were performed to find out thedifferences of the percentages of MDSC and TEMs as well as inflammatory cytokinesamong three groups.In the second part, from September2012to December201345patients withearly stage HCC who underwent microwave ablation in our department were recruitedin the study prospectively. Before MWA treatment, flow cytometry was used to detectthe percentages of MDSC and TEMs in peripheral blood, and Cytometric Bead Arraywas performed to measure serum levels inflammatory cytokines. All patients receivedMWA. The pathological factors and follow-up data after MWA were recorded.Statistical analyses were performed to study the association of clinical pathologicalfactors and the percentages of MDSC and TEMs in peripheral blood as well as serumconcentrations of cytokines with prognosis of the HCC patients.Results: In the first part,our data showed that compared with the healthy controls, thepercentages of MDSC in peripheral blood of the HCC patients was signifiicantlyelevated,and the percentage of MDSC in advanced-stage HCC patients is much higherthan that in early-stage HCC patients.Our data also showed that compared with thehealthy controls, the percentages of TEMs in peripheral blood of the HCC patientswas signifiicantly elevated. However, there was no significant difference betweenadvanced-stage group and early-stage group. Moreover, the percentage of TEMs inperipheral blood of advanced-stage HCC patients with portal vein tumor thrombuswas significantly higher than the patients without portal vein tumor thrombus.Ourdata also showed that compared with the healthy controls, the levels ofTh1-associated cytokineswas elevated in HCC patients, however, there were nosignificant differences between advanced-stage group and early-stage group. Thelevel of Th2-associated cytokines(IL-4) in HCC patients was significantly higher than that in healthy controls, moreover, the level of IL-4in advanced-stage group wassignificantly higher than that in early-stage group. Our data also showed comparedwith the healthy controls, the level of Th17-associated cytokine (IL-17A) wassignificantly elevated in HCC patients, and the level of IL-17A in advanced-stagegroup was significantly higher than that in early-stage group. Our data also showedcompared with the healthy controls, the level of Th22-associated cytokine(IL-22) wassignificantly elevated in HCC patients, and the level of IL-22in advanced-stage groupwas significantly higher than that in early-stage group.Accordingly, we selected thepercentages of MDSC and TEMs in peripheral blood and levels of IL-17A, IL-22inserum as the major reserch targets in th second part.In the second part, the ROC curve was used to evaluate the percentages ofMDSC, TEMs, and the value of IL-17A and IL-22for predicting post-treatmentrecurrence. The cutoff values of the percentages of MDSC,TEMs, IL-17A and IL-22were12.45%,15.15%,12.77pg/ml,85.54pg/ml respectively.The results of log-ranktests showed that AFP≥20ng/ml (P=0.023), Edmondson-Steiner III-IV stage(P=0.002),the percentage of TEMs≥15.15%(P＜0.0001), IL-22≥85.54pg/ml(P＜0.0001) were all associated with post-treatment recurrence. The results from themultivariate analysis showed that the percentage of TEMs≥15.15%(P=0.003),IL-22≥85.54pg/ml(P=0.011) were the independent prognostic factors ofpost-treatment recurrence.Conclusions:In this study we firstly sorted out four immune markers that havepotential value for indicating the initiation and development of HCC by analyzing thedata from20healthy controls and85HCC patients, then we found out that thepercentage of TEMs in peripheral blood and serum IL-22level were associated withpost-treatment recurrence. The percentage of TEMs in peripheral blood and serumIL-22level may be the potential targets for preventing the recurrence of HCCpatients.