The Influence Of Tils And PD-1/PD-L1 Expression On Prognosis Of Lung Adenocarcinoma Treated With TKI

Objective:Lung cancer originates from bronchial epithelium.Lung cancer is the most common cancer in the world,and is the most common cause of death from cancer worldwide.In China,the incidence and mortality of lung cancer ranks first in all malignant tumors.Among them,non-small cell lung cancer(NSCLC)accounts for about 85%,the 5 year survival rate is only about 15%.Lung adenocarcinoma accounts for about 50% of NSCLC.With the increasing of environmental pollution in recent years,the incidence of lung cancer is more and more high,which also poses new challenges to the treatment and evaluate the prognosis of lung cancer.Epidermal growth factor receptor(EGFR)mutation-positive lung adenocarcinoma is an important clinical subtype of NSCLC.It is generally believed that EGFR mutations account for 10% of patients with lung adenocarcinoma in the west,and up to 51.4% of patients with lung adenocarcinoma in Asian,especially higher in non-smoking Asian women,The mutation rate of EGFR was 51.8% in China.Pathological TNM staging is used to evaluate the development of postoperative disease,which is helpful to the formulation of the adjuvant treatment decision.However,the prognosis of the patients in the same stage is usually different.Therefore,it is significant to search for new predictive markers.Tumor infiltrating lymphocytes(TILs)which located mainly in the tumor microenvironment(TME)are a heterogeneous group of lymphocytes,and play an important role in the occurrence and development of tumor.Programmed death receptor-1(PD-1)is an inhibitory co-stimulatory molecule.PD-1 has two ligands PD-L1 and PD-L2.In tumor microenvironment,PD-L1 is the major ligand,and its expression is up-regulated.The binding of PD-1 on T cells and PD-L1 on tumor cells could negatively regulate the function of T cells,and promote the immune escape of tumor cells.However,the study of TILs and PD-1/PD-L1 in patients with EGFR mutation-positive lung adenocarcinoma is less,and the significance is not clear.Therefore,our study used immunohistochemical(IHC)method to explore the relationship between CD3,CD8,CD45 RO,Foxp3,PD-1,PD-L1 expression and prognosis in patients with lung adenocarcinoma treated with tyrosine kinase inhibitor(TKI).Methods:1 Immunohistochemistry was used to detect the expression of CD3,CD8,CD45 RO,Foxp3,PD-1 and PD-L1 in EGFR mutation-positive lung adenocarcinoma tissue.Correlation between TILs/PD-L1 expression and clinicopathological parameters was analyzed.2 The Spearman correlation was used to analyze the correlation between CD8+TILs and PD-L1 expression in EGFR mutation-positive lung adenocarcinoma tissue.3 Relationship between CD3,CD8,CD45 RO,Foxp3,PD-1,PD-L1 expression and prognosis in patients with EGFR mutation-positive lung adenocarcinoma was analyzed by Log-rank test and Cox proportional univariate analysis.Results:1 The expression of CD3,CD8,CD45 RO,Foxp3,PD-1 and PD-L1CD3,CD8,CD45 RO,Foxp3 and PD-1 were expressed mainly on tumor infiltrating lymphocytes.PD-L1 was expressed mainly on cancer cells and some interstitial cells.Of the 50 tissues with EGFR mutation-positive lung adenocarcinoma,25(50%)were positive for CD3 expression,23(46%)were positive for CD8 expression,23(46%)were positive for CD45 RO expression,23(46%)were positive for Foxp3 expression,24(48%)were positive for PD-1 expression,and 27(54%)were positive for PD-L1 expression.2 Correlation between CD8/PD-L1 expression and clinicopathological parametersThere was no significant association between CD8/PD-L1 expression and the clinicopathological variables3 The relationship between the expression of immune markers and the overall survival in patients with lung adenocarcinoma treated with TKIThe OS of patients with CD3 positive was significantly longer than that of those with CD3 negative(median OS,47 vs 42 months,P=0.039).The OS of patients with CD8 positive was significantly longer than that of those with CD8 negative(median OS,52 vs 42 months,P=0.030).The OS of patients with PD-L1 positive was significantly longer than that of those with PD-L1 negative(median OS,51 vs 41 months,P=0.002).However,the expression levels of CD45 RO,Foxp3 and PD-1 molecules were not related to OS(P=0.121,P=0.478,P=0.249).4 The Spearman correlation between PD-L1 expression and CD8+TILsElevated PD-L1 protein levels were positively correlated with the presence of CD8+TILs(P=0.044).Spearman's correlation coefficients were 0.286.5 Cox proportional univariate analysisLymph node staging(N),smoking,CD8 and PD-L1 were independent predictors of OS.Among them,N and smoking were risk factors(P=0.034,P=0.001),the risk ratios were 1.517 and 4.863.CD8 and PD-L1 molecules were protective factors(P=0.041,P=0.027),the risk ratios were 0.469 and 0.461.Conclusion:1 The expression of PD-L1 molecules was associated with longer OS in patients with lung adenocarcinoma treated with TKI.2 The expression of PD-L1 was positively correlated with CD8+TILs in patients with lung adenocarcinoma treated with TKI.3 The expression of CD8 and PD-L1 in patients with lung adenocarcinoma treated with TKI could be used as a positive predictive marker for OS.