IDO1 Expression Characteristics And Prognostic Value In Upper Urinary Tract Urothelial Carcinoma

Objective:In this study,we investigated the expression pattern and prognostic role of indoleamine 2,3-dioxygenase 1(IDO1)in upper tract urothelial carcinoma(UTUC)and further evaluated its relationship with clinicopathological characteristics,survival information and immue microenvironment in UTUC.Furthermore,we developed an IDO1-based immune classifier,We conducted this study to determine the prognostic role of IDO1 in UTUC and further construct an immune classifier,which can provide additional prognostic information and personalized treatment for UTUC.Methods:We obtained data from 173 UTUC tumor tissues from two independent cohorts,and then randomly divided the study population into training cohort and validation cohort at a ratio of 3:2.Take overall survival(OS)and disease-free survival(DFS)as the observation endpoints.The expression of IDO1,programmed cell death protein 1-ligand 1(PD-L1),programmed cell death 1(PD1)and the infiltration of immune cells(CD4+/CD8+/Foxp3+T cells)were assessed by immunohistochemical staining;The mRNA sequencing data were acquired from gene expression omnibus database,the hierarchical clustering and gene set enrichment analysis were measured to analyze the correlation between IDO1 and CD8+T cells exhaustion;The Kaplan-Meier curve and Log-rank test were used to compare survival differences of various factors,Cox regression model were used for prognostic analysis;The LASSO-logistic regression model was used to construct an IDO1-based classifier and time-dependent receiver operating characteristic curves and areas under the curves at 5 years were generated to assess prognostic accuracy.Results:1.High IDO1 expression on tumor cells indicated a poorer overall survival(OS)and disease-free survival(DFS)compared with low IDO1 expression in both cohorts.(OS:P=0.003,0,004 in the discovery cohort and validation cohort,respectively;DFS:P=0.013,0.006β in the discovery cohort and validation cohort,respectively)2.Patients with high expression of IDO1 on tumor cells possessed increased infiltration of Foxp3+ regulatory cells(P<0.001),CD4+T cells(P=0.044),CD8+T cells(P=0.004)and ratio of Foxp3+/CD8+(P=0.001).The prognosis of patients with high CD8+T cells infiltration is poor(P=0.010),and only in the group with high CD8+T cells infiltration,the expression of IDO1 on tumor cells has prognostic value(P=0.003).Moreover,high IDO1 expression on tumor cells possessed increased the expression of immune checkpoint related to exhaustion on CD8+T cells.3.The high expression of PD-L1 on immune cells is related to poor OS and DFS of tumor patients(OS:P=0.001β DFS:P=0.010)4.The distribution of IDO1 expression on tumor cells was irrelevant with that of PD-L1 expression on immune cells(P=0.51).5.An immune classifier based on CD8,IDO1 and PD-L1 has been developed,with its time-dependent receiver operating characteristic curves and area under the curves for OS at 5 years being 0.79(95%CI:0.65-0.93)in the discovery cohort and 0.75(95%CI:0.58-0.92)in the validation cohort.Moreover,the classifier exhibited a higher prognostic accuracy for 5-year OS than TNM stage and any other clinicopathological risk factors.Conclusion:As an independent predictor of the unfavorable clinical outcomes of UTUC,IDO1 expression on TC is expected to become a potential immunotherapy target.Our immune classifier based on IDO1 TC/CD8 TIL/PD-L1 IC expression status shows superior accuracy for survival prediction in UTUC,which could provide reliable markers for prognosis prediction,scientific basis for personalized risk stratification and clinical treatment decision-making of UTUC.