The Influence Of Immunologic Functions By Autologous CIK Cell Immunotherapy In Different Differentiation-stage Hepatocellular Carcinoma After Radical Resection

Objective: Primary liver cancer is one of the most common malignant tumors that severely threats people’s health in China.With the development of advanced therapeutic technology,a lot of treatments are currently available for hepatocellular carcinoma(HCC)in clinical.Radical hepatic tumor resection is still the main therapeutic method.However,the recurrent rate is very high and the 5-year survival rate is low(< 20-30%).Considering the different inhibition of immune status in HCC patient,the tiny residual will lead to tumor recurrence and metastasis in a short term,which will reduce the patient survival rate significantly.At the same time,the therapeutic methods such as radical resection and chemotherapy will reduce the immune function and influence the long-term therapeutic effect of HCC patient dramatically.Adoptive cellular immunotherapy is an effective therapeutic method to improve the patient’s immune state,especially for patients with malignant tumor.In principle,the patients’ autologous cells will be stimulated in vitro firstly by appropriate stimuli,and then,the active cells will be infused into patients’ blood to kill cancer cells.The aim of this study is to evaluate the therapeutic effectiveness of autologous CIK cell immunotherapy in HCC patients of different pathological stages after radical resection.Methods: A total of 60 patients that received radical hepatic tumor resection surgery during January 2013 to September 2015 in our hospital were included.According to the postoperative pathologic Edmonson-Steiner grading system,these patients were divided into two groups: one was well-differentiated or moderately-differentiated group that included 32 cases which the pathological stage was or Ⅰ Ⅱ,the other was poorly-differentiated group that included 28 cases which the pathological stage was ⅢorⅣ.All patients received autologous CIK cell immunotherapy.The general curative effects,the change of T lymphocyte subsets and Th1 / Th2 cytokines in peripheral blood before and after the treatment in both groups were observed,and the curative effect of CIK cell immunotherapy in HCC patients of different pathological grades were evaluated.Result:1 The changes of subsets of T-lymphocytes before and after cultured CIK cell.High-middle differentiation group and low differentiation group patients’ peripheral blood T lymphocyte have different changes before and after treatment.After cultured,the proportion of T cell subsets(CD3~+,CD3~+CD4~+,CD3~+CD8~+,CD3~+CD56~+)in the two groups were all increased with statistical difference(P<0.05).In which,the proliferation of CD3~+CD56~+ T cell subsets increased more significantly,with statistical differences between and within groups(P<0.05),the main effective cells of T lymphocyte of peripheral blood in patients with high-middle differentiation group were more easily amplified in the treatment of CIK.Meanwhile,the results showed that the CD4~+/CD8~+ ratio of peripheral blood was changed to >1 after culture in the low differentiation group of T lymphocytes.The results suggested that the immune function of liver cancer patients in low differentiation group was in the inhibitory states,however,status of immunosuppression could be reversed after cultured in vitro.2 The changes of subsets of T-lymphocytes before and after CIK treatment.High-middle differentiation group and low differentiation group patients’ peripheral blood T lymphocyte all have different changes before and after CIK treatments.Similarly,after treatment,the proportion of T cell subsets(CD3~+,CD3~+CD4~+,CD3~+CD8~+,CD3~+CD56~+)in the two groups were all increased,which has significant difference within the group(P<0.05).The proliferation of CD3~+CD56~+ T cell subsets increased more significantly,which has statistically significant differences between groups(P<0.05).After CIK immunotherapy,the high-middle differentiation group had higher reactivity,while low differentiation group had slightly worse for the treatment.Meanwhile,the results showed that although the immune function of low differentiation group was inhibited(CD4~+/CD8~+ ratio <1)before CIK treatment,it could be reversed(CD4~+/CD8~+ ratio >1)after CIK immunotherapy,low differentiated HCC patients could also benefit from CIK immunotherapy.3 Changes of Th1/Th2 cytokines in patients before and after treatment.There was a significant difference in Th1/Th2 Cytokines after treatment between the two groups.Th1-type cytokines,such as IL-2 and γ –IFN in the two groups of patients were significantly increased after treatment(P<0.05),and there were significant statistical difference between and within groups.And,Th2-type cytokine IL-6 in the two groups were declined after treatment,but the decreasing degree of the high-middle differentiation group was more significant than that of in the low differentiation group(P<0.05).4 Clinical observation: In the process of CIK immunotherapy,two groups of patients were both well tolerated.There were two patients in each group had mild fever and gastrointestinal reaction,but the symptoms disappeared within 8 hours without any treatment.After treatment,the subjective symptoms,appetite,sleep quality,capacity for action and willingness,emotion in the two groups of patients had significant improvements.Conclusions:1 CIK immune therapy can effectively improve the immune function of HCC patients with different pathological grade;2 After the cell cultured in vitro and the treatment of CIK immunotherapy,the T lymphocyte subsets increased in different differentiation-stage groups,especially in high-middle differentiation group;3 Th1 / Th2 cytokines tended to drift to Th1-type cytokines in HCC patients of different pathologic stage after CIK immunotherapy.