| Background: Gastric cancer is the most common malignant tumor of digestive tract in China. Despite of the development of various treatments such as surgery, chemotherapy, neoadjuvant chemotherapy and radiotherapy, the prognosis of gastric cancer patients at advanced stage still remains poor. The possibility of applying immunotherapy for gastric cancer would therefore be highly desirable. Adoptive cellular immunotherapy (ACI) have therapeutic activity in with high immunogenic tumor such as melanoma and kidney cancer, however, it's still unclear in gastric cancer.According to tumor immunoediting hypothesis, pre-existing immunity of gastric cancer patients is closely related to onset and progress of tumor and the poor prognosis. Therefore, establishing methods to assess pre-existing immunity and adding immunological parameters into the prognostic evaluation system of gastric cancer are significant to evaluate postoperative therapeutic strategy and efficacy.The immunological function of early postoperative patients is decreased significantly, and it is not suitable for applying systemic chemotherapy at this point. However, the tumor load in vivo is reduced to minimum. Therefore, it is suggested that early postoperative infusion of multiple immunologicly competent cells, such as DC, CIK and CTL, should improve immune function of patients and achieve more satisfactory results.Objective: This study was designed to establish methods for assessing pre-existing immunity of gastric cancer patients, establish database and prognostic evaluation system of gastric cancer patients after comprehensive treatment, and observe effect of early postoperative ACI on prognosis of gastric cancer patients.Methods: 1. The flow cytometric immune function assessing system was established, including detection of peripheral DC, Treg, memory T cells, NK, NKT, Th1/Th2, Tc1/Tc2 cells and intracellular cytokine (IFN-γand IL-4) by four-color flow cytometry; 2. Preliminary analysis of pre-existing immunity of preoperative gastric cancer patients (n=25) and healthy controls (n=25) was performed by detecting subsets of DC1 (Lin-DR+CDl11c+CD123-), DC2 (Lin-DR+CD11c-CD123+), NK (CD3-CD56+), NKT (CD3+ CD56+), Treg (CD4+CD25+FOXP3+), CD4+TCM (CD4+CD45RO+CCR7+CD45RA-), CD4+TEM (CD4+CD45RO+CCR7-CD45RA-), CD8+TCM (CD8+CD45RO+CCR7+CD45RA-), CD8+TEM (CD8+CD45RO+CCR7-CD45RA-), Th1 (CD4+IFN-γ+), Th2 (CD4+IL-4+), Tc1 (CD8+IFN-γ+) and Tc2 (CD8+IL-4+) cells in peripheral blood; 3. A retrospective database of 93 gastric cancer patients following surgical treatment combined with chemotherapy and/or immunotherapy from December 2004 to March 2008 was constructed firstly. Data were censored at time of death, loss to follow-up or January 1st, 2009. Survival was estimated using the Kaplan-Meier method. The factors affecting the survival time were evaluated by Cox proportional hazard model and Log-Rank test.Results: 1. The results of preoperative gastric cancer patients show: the CD4+CD25+FOXP3+ Treg of gastric cancer patients were significantly higher than the normal control group (1.993±0.830% Vs 1.229±0.656%, P <0.01); the ratios of Th1/PBL, Tc1/PBL, Th1/Th2 and Tc1/Tc2 in gastric cancer patients were significantly lower than the normal control group (3.047±1.710 % Vs 6.242±4.078 % , 6.393±5.235 % Vs 14.171±8.984 %, 1.215±0.219 % Vs 2.552±2.343 %, 1.306±0.289 % Vs 17.200±25.930 %, P<0.05); the CD4+TCM, CD4+TEM, CD8+Tcm of gastric cancer patients were significantly higher than the normal control group (4.585±2.502% Vs 2.765±1.942%, 18.682±7.374% Vs 13.032±4.059 %, 0.455±0.472% Vs 0.127±0.165%, P <0.05), but there was no significant difference of CD8+TEM between them (8.379±3.431% Vs 8.733±3.048%, P> 0.05); there was no significant difference of DC1, DC2 and DC1/DC2 in peripheral blood between gastric cancer patients and normal control (0.201±0.095% Vs 0.198±0.087%, 0.081±0.032% Vs 0.093±0.046%, 2.693±1.636% Vs 2.561±1.486%, P> 0.05); there was no significant difference of NK and NKT in peripheral blood between gastric cancer patients and normal control (19.209±14.116% Vs 20.306±8.844%, 8.481±5.378% Vs 6.156±3.934%, P> 0.05). 2. Complete follow-up data were obtained from 68 cases of patients, majority of who were advanced stage ones. In total, 35 patients died, giving median survival time of 21 months. The estimated 3-year overall survival was 36%. In univariate analysis, age, clinical stage, type of surgery and early postoperative adoptive immunotherapy (less than 14 days after operation) were significant prognostic factors related to overall survival time (P <0.05). Gender, histopathologically diffuse type, adjuvant chemotherapy and numbers of immunotherapy were found to have no effect on survival (P> 0.05). In multivariate analysis, age, radical surgery, clinical stage, early postoperative adoptive immunotherapy (less than 14 days after operation) were found to be the statistically significant prognostic factors related to survival (P <0.05).Conclusion: 1. The flow cytometric immune function assay was a stable method for assessing pre-existing immunity of gastric cancer patients; 2. The pre-existing immunity was poor in preoperative gastric cancer patients, which might be related to the onset and progress of tumor and the poor prognosis. Immunological parameters might be useful predictors to evaluate prognosis of gastric cancer patients; 3. The factors including age, clinical stage, radical surgery and early postoperative adoptive immunotherapy had significant effect on survival of postoperative gastric cancer patients. Early postoperative adoptive immunotherapy couid be a beneficial adjuvant therapy to improve clinical outcomes of gastric cancer patients. |
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