CXCL5 Predict The Efficacy Of Neoadjuvant Immunotherapy For Esophageal Cancer And Its Correlation With Tumor Microenvironment

Background and objective:Although the therapeutic effective of esophageal cancer has been improved under the multidisciplinary diagnosis treatment model in recent years,there are still a majority of patients face the risk of recurrence and distant metastasis.Immunotherapy undoubtedly provides a new insight expected to solve this problem.The effectiveness of immunotherapy for esophageal cancer has been reported.However,there are still part patients are insensitivity for immunotherapy,so it is urgent to find effective biomarkers to screen potential patients who could benefit from immunotherapy.Methods:Patients with locally advanced esophageal squamous cell carcinoma（ESCC）were enrolled.After enrollment,all patients received neoadjuvant toripalimab（240 mg,d1）combined paclitaxel（135 mg/m2,d1）and carboplatin（AUC 5 mg/m L/min,d1）,every 3 weeks for a total of 2 cycles.And then the surgery would be performed within4 to 6 weeks after neoadjuvant therapy.The primary end points were safety,feasibility and major pathological response（MPR）rate,and the secondary end points were pathological complete response（p CR）rate,disease-free survival and overall survival.Then,the whole-exome sequencing and RNA sequencing would be performed to detecting the specimens before the treatment,and then the genomic mutations of ESCC would be analyzed with bioinformatics in order to finding the biomarkers that could predict the effective of neoadjuvant immunochemotherapy.And then,multiple immunofluorescence would be performed to demonstrating the changes of tumor microenvironment before and after immunotherapy for ESCC.In addition,CXCL5 overexpressed cells would be constructed in vitro,and the impacts of CXCL5 on the biological behavior of esophageal cancer will be verified by Western-blot,RT-PCR and Transwell experiments.Results:1.Twenty resectable ESCC patients were enrolled,sixteen patients finished whole treatment regimen.And 4（20%）patients experienced 3 grade treatment-related adverse events（AEs）with neoadjuvant immunochemotherapy.The rate of p CR was 18.8%and the rate of MPR was 43.8%.2.CXCL5 was higher expression in the response group than non-response group by RNA sequencing,and the AUC of CXCL5 expression to predict the efficacy of neoadjuvant immunochemotherapy was 0.9（P<0.001）.3.After neoadjuvant immunochemotherapy,the tumor microenvironment including the expression of PD-L1 and the degree of infiltration lymphocytes were altered.Such as CD8+T cells were significantly increased and the infiltration of M2-TAM was significantly decreased after treatment.4.CXCL5 overexpression can enhance the migration and invasion of esophageal cancer,and increase the expression of PD-L1 on the esophageal cancer cells.Conclusion:Toripalimab combined with chemotherapy is safety,efficacy and feasibility in the treatment of ESCC.CXCL5 is a potential biomarker for predicting the efficacy of immunotherapy,but it needs further validation in large sample trials.