The Expression And Clinical Significance Of PD-1 And PD-L1 In Stage ?a-N2 Non-Small Cell Lung Cancer

Objective:The present study evalutated the expression of PD-1 and PD-L1 in stage ?a-N2 non-small cell lung cancer(NSCLC),analyzed the correlation between the two indicators and the clinicopathological features,explored the mechanism of PD-1/PDL1 pathway to promote the development of NSCLC by analyzing the correlation between PD-L1 and PD-1 expression with the expression of Akt?mTOR and HIF-1?,and finally evalutated the prognostic significance of PD-L1 and PD-1 expression in stage ?a-N2 NSCLC,aiming to search for the best benefit group for immunotherapy and provide more accurate guidance for the treatment of patients.Method:1.We used immunohistochemistry(IHC)to detect the expression of PD-L1 and PD-1 in 102 patients with stage ?a-N2 NSCLC,and also in 21 cases of adjacent tissue specimens which was away from tumor tissues more than 5cm.Then we analyzed the correlation between the two indicators and the clinicopathological features,and evalutated the prognostic significance of them in stage ?a-N2 NSCLC.2.Moreover,we used IHC to detect the expression of Akt?mTOR and HIF-1? in NSCLC,analyzed the correlation between the three indicators and the clinicopathological features,and explored the correlation between them and PD-L1 and PD-1 expression,aiming to study the mechanism of PD-1/PD-L1 pathway to promote the development of NSCLC.Results:1.The positive expression rate of PD-L1 in tumor cells and in tumor interstitial cells was 58.8%(60/102)and 65.7%(67/102),respectively.Positive PD-1 expression in tumor infiltrating lymphocytes(TILs)was found in 46 cases(45.1%).Neither the expression of PD-L1 nor PD-1 were found in 21 cases of adjacent tissues.PD-1 expression in TILs was significantly correlated with PD-L1 expression in both tumor cells and tumor interstitial cells(P=0.016,?2=5.770;P=0.045,?2=4.021).2.The expression of PD-L1 in tumor cancers was significantly correlated with tumor location(P=0.012),the number of N2 positive lymph node stations(P=0.000),the positive rate of N2 metastatic lymph nodes(P=0.019),and the status of subcarinal lymph node(P=0.000).There was a significant correlation between the expression of PD-1 in TILs with T stage(P=0.037),the number of N2 positive lymph node stations(P=0.005)and the positive rate of N2 metastatic lymph nodes(P=0.000).3.The positive expression rates of Akt,mTOR and HIF-1? in NSCLC were 72.5%,43.1% and 82.4%,respectively.The expression of PD-L1 in tumor cells was significantly correlated with the expression of Akt(?2=4.062,P=0.044),mTOR(?2=4.322,P=0.038)and HIF-1?(?2=5.863,P=0.015).And the expression of PD1 in TILs was significantly correlated with the expression of Akt(?2=4.257,P=0.039),mTOR(?2=4.293,P=0.038)and HIF-1?(?2=4.620,P=0.032).4.The 5-year OS rates of the PD-L1 positive group and the negative group were 37.3% and 60.3% respectively(P=0.003);and the 5-year OS rates of PD-1 positive group and negative group were 37.9% and 55.1%(P=0.046),respectively.However,neither PD-L1 expression in tumor cells nor PD-1 expression in TILs had significant effect on DFS(P=0.095;P=0.346).5.Subgroup analyses identified PD-L1 expression in tumor cells to be associated with poor prognosis for age(?65,P=0.004),tumor location(right lung,P=0.021),tumor histology(squamous cell carcinoma,P=0.035)and T stage(T1,P=0.035;T2,P=0.017;T3,P=0.000).The expression of PD-1 in TILs was significantly correlated with poor prognosis for tumor histology(squamous cell carcinoma,P=0.003),T stage(T1,P=0.000;T3,P=0.000),and the number of patients with N2 positive lymph node stations(single station,P=0.045).6.For all patients,the 1-,3,and 5-year DFS were 37.3%,35.2% and 30.2%,respectively,with a median DFS of 9.6 months.The 1-,3,and 5-year OS were 82.3%,49.5% and 47.2%,respectively,with a median OS of 35.1 months.Univariate analysis showed that N2 positive lymph node stations(P=0.014),the number of N2 positive lymph nodes(P=0.009),the positive rate of N2 metastatic lymph nodes(P=0.007),the status of subcarinal lymph nodes(P=0.000),PD-L1 expression in tumor cells(P=0.030)and PD-1 expression in TILs(P=0.046)were prognostic factors affecting OS.Multivariate analysis showed only the status of subcarinal lymph nodes was an independent factor affecting OS(HR = 2.364,95% CI: 1.139-4.905,P = 0.021).Conclusions:1.The expression of PD-L1 or PD-1 in NSCLC tissues was significantly higher than that in adjacent tissues.There was a significant positive correlation between PDL1 in tumor cells and PD-1 expression in TILs.2.The expression of PD-L1 in tumor cells was significantly correlated with tumor location,the number of N2 positive lymph node stations,the positive rate of N2 lymph nodes and the status of subcarinal lymph node,which suggests that PD-L1 expression can promote lymph node metastasis by inhibiting anti-tumor immune response,thus affecting the prognosis of patients.It also suggests that PD-L1 expression may help to predict the lymph node metastasis pattern in patients with stage ?a-N2 NSCLC,thus can provide more information on the stratified treatment of this group of patients.3.There was a co-expression between PD-L1 and Akt,mTOR or HIF-1? in tumor cells,suggesting that PD1/PD-L1 may promote the development of NSCLC by affecting Akt,mTOR or HIF-1 pathway.Blocking PD-1/PD-L1 pathway and Akt/mTOR or Hif-1? pathways simultaneously may be used as a new strategy for tumor immunotherapy.4.The expression of PD-L1 and PD-1 were poor prognostic factors affecting OS of patients.PD-L1 and PD-1 expression may become new markers for individual treatment of patients with stage ?a-N2 NSCLC.