| Objective: Gastric cancer(GC)is one of the most common malignant tumors of digestive system in China.According to the 2012 Global Tumor Epidemiology Statistics(GLOBOCAN2012),GC is the fifth most common cause of cancer and the third most frequent cause of cancer-related death,in both sexes,all over the world.In China,GC is the third most common cause of cancer and the second most frequent cause of cancer-related death.About400000 new cases of GC occur in China each year,accounting for 42% in the world.It often presents late in life,bearing a poor overall survival.The survival time is also short.General treatments consist surgery,radiotherapy and chemotherapy.Patients with advanced GC had a low cure rate and poor outcome.In recent years,the progress and clinical efficacy of immunotherapy make it a new treatment model.Immunotherapy includes T-cell adoptive therapy,tumor vaccines,toll-like receptor agonists and immune checkpoint inhibitors,etc.The immune checkpoint inhibitors play an important role of all.At present,the study is at an early stage,such as programmed cell death-1(PD-1)and programmed cell death ligand 1(PD-L1).PD-1/PD-L1 is an inhibitory pathway in the immune system.It plays an important role in in regulating the duration and magnitude of the physiological immune response and maintaining immune tolerance.Thus avoiding the immune response to normal tissue damage.In addition,the inhibitory checkpoint is regulated by the interaction of receptor/ligand,and may be involved in the process of tumor immune escape.Previous studies on PD-1 and PD-L1 focused on solid tumors such as lung cancer and melanoma,and have achieved some clinical efficacy.Two anti-PD-1 monoclonal antibodies,Nivolumab and Pembrolizumab,have been approved for the clinical treatment of advanced squamous non-small cell lung cancer and non-resectable/metastatic melanoma by FDA.But the treatment of GC is still lack of evidence.To investigate the correlation between the expression of PD-L1 and its receptor PD-1 in GC as well as clinicopathologic features and prognosis of GC patients.Methods: Eighty-two patients of III or IV stage according to the pathological TNM,who received gastrectomy at the Fourth Hospital of He Bei Medical University from January 2007 to December 2007 were enrolled in this study.The tumor paraffin tissue samples and clinical features are collected,including age,sex,tumor size,degree of differentiation,tumor site(gastrectomy site),depth of tumor invasion,tumor vascular suppositories,with or without lymph node metastasis and presence of distant metastasis pre-operation.The living conditions of the 82 patients were followed by telephone.The expression of PD-1/PD-L1 in tumor tissues was detected by immunohistochemistry.The expression of PD-1 and PD-L1 was assessed on the basis of the product of staining intensity classification and positive cell density classification.SPSS 21.0 statistical software was employed to analyze all the data.Chi-square test analyzed the expression of PD-1 and PD-L1 as well as clinicopathologic features.Kaplan-Meier analyzed the survival curve and Log-Rank inspected whether the difference of survival rates had statistical significance.The relationship between clinicopathologic features and prognosis was analyzed by univariate and multivariate COX regression survival analysis.The difference was statistically significant(P<0.05).Results:1 In all GC tissues,42.68% showed positive PD-L1 expression,mainly located in cytoplasm and cell membrane of cancer cells and tumor infiltrating lymphocytes.Interstitial lymphocytes presented small circle,less nuclear blades and some sample distribution under the microscope.The positive rate of cellular and intercellular PD-L1 expression was respectively 32.93% and21.95%.Of all cases,13.41% showed positive PD-1 expression,which mainly located in cytoplasm and cell membrane of tumor infiltrating lymphocytes(TIL).The positive rate of PD-1 expression was lower than that of PD-L1 expression in tumor tissues.Forty-three cases of GC showed neither PD-1 nor PD-L1 expression.2 The negative and positive rate of cellular PD-L1 expression in patients with negative PD-1 expression were respectively 70.42% and 29.58%.The negative and positive rate of cellular PD-L1 expression in patients with positive PD-1 expression were respectively 45.45% and 54.55%(P>0.05);The negative and positive rate of intercellular PD-L1 expression in patients with negative PD-1 expression were respectively 77.46% and 22.54%.The negative and positive rate of intercellular PD-L1 expression in patients with positive PD-1 expression were respectively 81.82% and 18.18%(P>0.05).PD-1 protein expression in GC tissues had no significantly correlation to PD-L1 in cancer cells and tumor infiltrating lymphocytes.3 The positive rate of PD-1 expression in patients with and without distant metastasis was respectively 42.86% and 3.28%(P<0.05).The positive rate of cellular PD-L1 expression in patients with and without distant metastasis was respectively 90.48% and 13.11%(P<0.05).The positive rate of intercellular PD-L1 expression in patients with and without distant metastasis was respectively 47.62% and 13.11%(P<0.05).PD-1 expression and PD-L1 expression in GC tissues were closely related to the presence of distant metastasis and the depth of tumor infiltration.The intercellular PD-L1 expression was closely related to the degree of tumor differentiation.However,PD-1 expression and PD-L1 expression in GC tissues had no significantly correlation to patient’s age,sex,tumor size,tumor location and tumor vascular suppositories.4 The clinicopathological features that might influence the prognosis of patients were analyzed by univariate COX regression,such as age,sex,tumor size,the degree of differentiation,the gastrectomy site,tumor vascular suppositories,the depth of tumor infiltration,PD-L1 protein over-expression and the presence of distant metastasis,etc.The result showed that the gastrectomy site,the presence of distant metastasis and PD-L1over-expression were the adverse factors affecting the prognosis of patients with GC(P<0.05).At the same time,multivariate COX regression survival analysis showed that the cellular PD-L1 expression and the presence of distant metastasis were independent factors affecting patient’s survival.Kaplan-Meier survival curve analysis showed that cellular PD-L1 expression was significantly correlation to prognosis.The postoperative survival of patients who had positive PD-L1 expression was shorter than the negative ones,and the Log-Rank test showed that the difference was statistically significant(P<0.05).The intercellular PD-L1 expression and PD-1 expression in GC tissues had no significantly correlation to prognosis.Conclusion:1 PD-1 and PD-L1 molecules can be expressed in gastric cancer tissues.PD-L1 expression was mainly located in cytoplasm and membrane of cancer cells and tumor infiltrating lymphocytes.PD-1 expression was mainly located in cytoplasm and cell membrane of tumor infiltrating lymphocytes.2 PD-1 expression and PD-L1 expression in gastric cancer were closely related to the presence of distant metastasis and the depth of tumor infiltration.There was no significantly correlation to patients’ age,sex,tumor size,tumor location and tumor vascular suppositories.3 The postoperative survival of patients who were PD-L1 positive expression was shorter than the negative ones.It showed that PD-L1 expression was an independent factor affecting the prognosis of patients.PD-1expression had no significantly correlation to postoperative survival. |
