Changes In Tumor Expression Of IDO 1 And PD-L1 After Neoadjuvant Therapy In Patients With Esophageal Squamous Cell Carcinoma And Its Clinical Significance

Background and ObjectiveNeoadjuvant chemoradiotherapy or chemotherapy followed by radical surgery has become the standard of care for locally advanced resectable esophageal squamous cell carcinoma(ESCC),but few specific biomarkers were available as a means of evaluating efficacy.Indoleamine 2,3-dioxygenase(IDO1)and programmed cell death protein-ligand 1(PD-L1)play an important role in immune evasion of tumor cells.There were few studies focused on the changes of tumor IDO1 and PD-L1 expression after neoadjuvant therapy in ESCC.Here we investigated the changes of tumor expression of IDO1 and PD-L1 after neoadjuvant chemoradiotherapy(NCRT)and neoadjuvant chemotherapy(NCT)in ESCC respectively,and evaluate the potential predictive value of the changes of tumor IDOl and PD-L1 expression on pathologic response and clinical outcome.Material and MethodWe retrospectively recruited 295 ESCC patients who received NCRT or NCT followed by curative surgery between October 2012 and November 2018 in our hospital,including 278 patients with NCT and 17 patients with NCRT.By matching propensity scores in 295 patients,we finally recruited 85 ESCC patients,including 17 patients with NCRT and 68 patients with NCT.Tumor IDO 1 and PD-L1 expression in paired specimens were evaluated by immunohistochemistry,and calculated by multiplying the intensity of expression(0,no expression;1,weak expression;2,moderate expression;or 3,strong expression)and proportion of stained cells(0-100%),Wilcoxon rank test was used to evaluate the intra-group changes,and the differences in changes of IDO1 and PD-L1 expression score between two groups were evaluated by Mann-Whitney U-test.Survival time distribution was evaluated by the Kaplan-Meier method,and compared by the log-rank test.Cox proportional hazard model was constructed for univariate and multivariate survival analyses.Result1.In the NCRT group,Wilcoxon rank test indicated no significant difference in tumor IDO1 expression score before and after NCRT(p=0.440).However,the median IDO1 expression score significantly increased after NCT(0 vs 15,p=0.002).2.In the NCRT group,the median tumor PD-L1 expression score significantly increased after neoadjuvant therapy(0 vs 30,p=0.007).There was no significant difference in the median score of tumor expression of PD-L1 before and after NCT(p=0.968).3.Tumor IDO1 expression increased after neoadjuvant therapy significantly associated with poor pathological response(p=0.002),NCT(p=0.009),pN+(p=0.029),poor pathological TNM staging(Ⅲ/Ⅳ)(p=0.031),nerve invasion(p=0.015)and vascular cancer embolus(p=0.019);and not associated with gender,age,tobacco use,alcohol use and clinical tumor TNM staging.4.Tumor PD-L1 expression increased after neoadjuvant therapy significantly associated with NCRT(p=0.001),and not associated with gender,age,tobacco use,alcohol use,clinical tumor TNM staging,pathological response,pN+,pathological tumor TNM staging,nerve invasion and vascular cancer embolus.5.In Kaplan-Meier survival analysis,patients with tumor IDOl increased after neoadjuvant therapy achieved significantly poorer overall survival(OS)and disease-free survival(DFS)than patients with tumor IDO1 not increased;patients with tumor PD-L1 increased after neoadjuvant therapy also achieved significantly poorer OS and DFS than patients with tumor PD-L1 not increased.Multivariate analysis displayed that tumor IDO1 or PD-L1 expression increased after neoadjuvant treatment was independent poor prognostic factors.ConclusionNCT could promote tumor IDO1 expression,NCRT could upregulate tumor PD-L1 expression,and tumor IDO1 or PD-L1 expression increased after neoadjuvant therapy predicts poor prognosis in ESCC.