Research On The Prognostic Significance Of Systemic Immune-inflammation Index And Tumor Infiltrating Lymphocytes In Nasopharyngeal Carcinoma

Part ?Title:Pretreatment Systemic Immune-inflammation Index Predicts Survival for Non-metastatic Nasopharyngeal Carcinoma:Two Independent Institutional StudiesObjective:The purpose of this study is to evaluate the prognostic value of systemic immune-inflammation index(SII)in non-metastatic nasopharyngeal carcinoma.Materials and Methods:We retrospectively analyzed the data of 839 patients with non-metastatic NPC collected from two independent institutions.One cohort consisting of 459 patients was defined as training setting and patients from the other institution was assigned as external validation cohort.Based on the training cohort,receiver operating characteristic(ROC)was used to define the optimal cutoff value of SII.Kaplan-Meier survival curve was used to perform the survival analysis.Univariate and multivariate analyses were conducted with Cox proportional regression model,and a stratification prognostic risk model was established based on multivariate results.SII expression and prognostic risk stratification model were externally validated in the validation cohort.and a prognostic risk stratification model were developed based on training cohort and were further assessed in validation cohort.In addition,propensity score matching(PSM)was respectively performed in each cohort to minimize the confounding effects of unbalanced covariables.Results:The optimal cutoff value of SII was 686 in the training cohort.Before PSM,multivariate analysis showed that higher SII(SII>686,SII-H)was independently associated with worse progression free survival(PFS)in both training and validation cohort(hazard ratio(HR),1.64,95%confidence interval(CI)1.15-2.33 and HR 1.72,95%CI 1.16-2.55,respectively).After PSM,SII was revealed to be an independent determinant for PFS in two cohorts.Based on two independent prognostic factors of SII and N stage,a categorical risk stratification model was developed.Based on the independent prognostic factors affecting PFS,we constructed a prognostic risk stratification model including SII and N stage.According to the number of risk factors,the study cohort was divided into low-risk(0 risk factors),intermediate-risk(1 risk factor),and high-risk(2 risk factors)groups.It demonstrated significant discrimination among risk stratification in terms of PFS and DMFS in training cohort.No significantly different PFS was found between RT alone and combined modality of therapy within low-and intermediate-risk group.In the high risk group,patients receiving concurrent chemoradiotherapy had superior PFS than those receiving other therapeutic modalities.Conclusion:Pretreatment SII represents a promising predictor of PFS in non-metastatic NPC patients.The prognostic risk stratification incorporating SII is instructive for tailored treatment decision making.Part ?Title:Prognostic Significance of Tumor Infiltrating Lymphocytes and Programmed Cell Death-ligand 1 in Nasopharyngeal CarcinomaObjective:Tumor microenvironment(TME),composed of tumor cells and the surrounding matrix,is an important place for the growth of tumor cells.In the TME,different types of tumor infiltrating lymphocytes(TILs)have different roles in the occurrence and progression of tumors.The differences in subtypes,composition,and spatial distribution of TILs have been proved to be related with clinical prognosis,and at the same time,it is also the key factor for the effectiveness of immunotherapy.The role of programmed cell death-ligand 1(PD-L1)and different subtypes of TILs in nasopharyngeal carcinoma(NPC)are till poorly studied.The purpose of this study is to evaluate the prognostic significance of TILs and immune checkpoint protein expression in NPC.Methods:A total of 121 NPC patients consisting of 68 prognosis better(Group 1)and 53 prognosis poor(Group 2)treated between 2010 to 2014 were included.Archival tumor tissues of selected patients were retrieved and a tissue microarray(TMA)was constructed.The TMA was stained with CD3,CD4,CD8,Foxp3,CK,PD-L1 and DAPI by using multiplexed quantitative fluorescence.Continuous variables were divided into dichotomous variables using the median of density expressed by PD-L1 and TILs.The density differences and association with survival of PD-L1 and TILs were analyzed between two groups.Results:In the tumor cells,PD-L1 positive rate was 96%.In the immune cells,PD-L1 positive rate was 98.4%.PD-L1 positive immune cells(ICs-PDL1)were significantly correlated with high infiltration of CD3+TILs,CD4+Teff,CTLs,and Treg.Patients with high PDL1+Treg had unfavorable overall survival(OS)and disease free survival(DFS)(HR 2.093,95%CI 1.038-4.222,p=0.035 and HR 2.501,95%CI 1.421-4.403,p=0.001).Although high PD-L1 positive tumor cells(TCs-PDL1)expression was associated with favorable OS and DFS,the differences were unobvious(p=0.055 and p=0.078).Meanwhile,patients with low Treg/CTL ratio had better overall survival(OS),but there was no statistical differences(p=0.082).In addition,high density of Treg,Treg/CTL ratio and Treg/CD4+Teff ratio were significantly associated with poor survival of DFS(p=0.027,p=0.001,p=0.004,respectively).Conclusion:Our study indicated that higher density of Treg,Treg/CTL ratio and Treg/CD4+Teff ratio were associated with worse survival of NPC which may contribute to the formation of immunosuppressive microenvironment.PD-L1 expression on TCs was a favorable factor in NPC patients.