Perioperative Immuno-inflammation Status In Hepatocellular Carcinoma Patients Receiving Liver Transplantation: Acute Rejection May Predict Better Prognosis

Objective & Background:An analysis of acute rejection(AR)after liver transplantation in the 2011 Annual Report of the China Liver Transplant Registry(CLTR)revealed the novel finding that the incidence of AR after liver transplantation was significantly higher among patients with benign end-stage liver disease(BESLD)(10.82%,1299/12003)compared with patients with hepatocellular carcinoma(HCC)(8.68%,770/8874)(?2=26.299,P<0.001).However,the reasons for the lower incidence of AR after liver transplantation in HCC patients remain unclear.Recent studies demonstrated that exhaustion of T cells,which are a dominant factor in rejection after transplantation,play an important role in the occurrence and development of liver cancer.Cancer cells,inflammatory cells,and suppressive cytokines in the tumor microenvironment constitute a complex immunosuppressive network,regulating T-cell phenotype and function and driving T cells to differentiate terminally into ‘exhausted' T cells.We therefore speculated that a degree of preoperative immunosuppression exists in HCC patients,which continues after liver transplantation,thus reducing the incidence of postoperative AR.We aimed to verify this speculation by analyzing the correlation between immuno-inflammation status and postoperative AR and prognosis in a retrospective study of patients who received liver transplants for hepatitis B virus(HBV)-related HCC or BESLD.Methods:The development of AR in patients received liver transplantation due to HBV-related HCC and HBV-related BESLD in the Organ Transplantation Institute,Changzheng Hospital,The Naval Military Medical University from September 1,2008 to April 1,2017 were retrospectively analyzed,and followed up until April 1,2018.For HCC recipients with AR(AR group),according to tumor stage and immunosuppressant concentration,HCC liver transplant recipients without AR were paired at 1:3 ratio(non-AR group).The perioperative immune function and prognosis of HCC patients in the two groups were studied.Results:Part 1 Comparison of perioperative immuno-inflammation between HCC and BESLD patients received liver transplantation with ARBy comparing the consistency between the incidence of AR after liver transplantation in this study and that shown in CLTR,it was found that the overall incidence of AR in patients with HCC and BESLD was 8.60%(32/372)and 10.61%(24/226)respectively.The incidence of AR in HCC patients was significantly lower than that in BESLD patients(3.23% vs.7.08%,?2 = 4.679,P=0.031)28 days after operation.Therefore,we tried to predict the data situation of a large sample nationwide through the case data of our center.Therefore,we compared the preoperative,perioperative and postoperative data between the HCC group and the BESLD group in our center,and found that the Rejection Activity Index(RAI)score of the HCC group was significantly lower than that of the BESLD group(t=-2.134,P=0.047),and the perioperative CD4/CD8 ratio was significantly lower than that of the BESLD group(F=16.367,P<0.001).This is consistent with our hypothesis that preoperative HCC patients have a certain degree of immunosuppression.Part 2 A matched study and analysis of preoperative immuno-inflammation and prognosis of HCC patients received liver transplantation with ARAccording to the tumor stage and immunosuppressant concentration,the maximum matching principle was adopted to match the non-ar group in the AR group,and the baseline was kept consistent as far as possible.When the matching reached 1:4,there were no matching cases,so the ratio of 1:3 was finally selected.We collected all the current indicators used to describe the immune function status of liver cancer.It was found that the later the tumor stage in HCC patients,the higher systemic immune inflammation index(SII or P×N/L),neutrophil/lymphocyte ratio(NLR or N/L),monocyte/lymphocyte ratio(MLR or M/L),and platelet/lymphocyte ratio(PLR or P/L),and the lower CD4/CD8 were observed before operation.Among them,preoperative M/L was the independent risk factor of survival time and recurrence free survival after liver transplantation in HCC patients(RR=3.558,P=0.026;RR=11.287,P<0.001).Then we compared the postoperative tumor recurrence and survival of the AR group and the non-AR group under different tumor loads,and found that the 1-year,3-year and 5-year survival rates were 76%,71% and 53 % respectively in the AR group,and were 67%,37% and 25% respectively in the non-AR group(?2=4.134,P=0.042).This may indicate that acute rejection after hepatocellular carcinoma liver transplantation indicates a better prognosis.Conclusion:Preoperative immunosuppression exists in HCC patients to some extent,which continues after liver transplantation,and reduces the incidence of postoperative AR.The occurrence of AR in HCC patients after liver transplantation may indicate a better prognosis.