| Backgroud and Objective:Esophageal squamous cell carcinoma(ESCC)is a common malignant tumor with high morbidity and mortality in China.The curative effect and prognosis of advanced ESCC are even worse.A number of III clinical studies have shown that first-line programmed cell death protein-1(PD-1)immune checkpoint inhibitor combined with chemotherapy significantly prolonged the median survival time of advanced ESCC.However,the efficacy and differences of different ESCC inhibitors in real-world first-line PD-1 inhibitor immunosuppressive regimens are not clear.Programmed cell death protein ligand-1(PD-L1)state prediction of the efficacy and prognosis of immunotherapy is not perfect,these advanced ESCC first-line treatment in the immune-related clinical problems need to be solved.Part Ⅰ:We retrospectively analyzed the efficacy of Camrelizumab or Sintilimab combined with chemotherapy in the first-line treatment of patients with advanced esophageal squamous cell carcinoma(ESCC),to verify the efficacy and differences of different PD-1 checkpoint inhibitors(Camrelizumab or Sintilimab)combined with chemotherapy in the first-line treatment of advanced ESCC patients in the real world.The purpose of this study is to provide data reference for the application of clinical first-line PD-1 immunotherapy combined with chemotherapy in patients with advanced ESCC and the selection of different PD-1 immunotherapeutic drugs with Camrelizumab or Sintilimab.Part II:By analyzing the effect of ECRG4 on ESCC tumor immune microenvironment,to analyze the expression characteristics of ECRG4 in ESCC tumor immune microenvironment,and the correlation between ECRG4 and immune ce ll infiltration and immune checkpoint gene expression,to explore the possible molecular mechanism of ECRG4 regulating the immune cellular immune effect of ESCC tumor immune microenvironment,and to provide theoretical basis for ECRG4 as a potential candid ate biomarker for predicting the efficacy of advanced ESCC immunotherapy.Methods:Part Ⅰ:60 patients with advanced ESCC diagnosed in Henan people’s Hospital from January 2020 to October 2022 were collected and analyzed.The first-line treatment regimen was treated with Camrelizumab or Sintilimab combined chemotherapy.Chi-square test was used to analyze the difference between the two groups,and R Software survival package was used to analyze the survival difference.Cox proportional hazard regression analysis was used to screen the possible prognostic factors of OS and PFS in advanced ESCC pa tients who received first-line PD-1 checkpoint inhibitors(Camrelizumab or Sintilimab)combined with chemotherapy.Part II: By mining TCGA public database and using bioinformatics network tools to analyze the effect of ECRG4 on ESCC tumor immune microenviron ment,using survival analysis and ECRG4 gene expression and other clinicopathological parameters to establish a line chart and construct an ESCC prognosis prediction model.Differential expression was used to analyze the expression characteristics of ECRG4 in ESCC tumor immune microenvironment.Immune microenvironment,immune cell infiltration and immune checkpoint gene were used to analyze the correlation between ECRG4 and immune cell infiltration and immune checkpoint gene expression.Gene coexpression analysis,GO and KEGG enrichment analysis and GSEA enrichment analysis were used to explore the possible molecular mechanism of ECRG4 regulation of immune cellular immune effect in ESCC tumor immune microenvironment.Results:Part Ⅰ:60 patients with advanced ESCC were treated with PD-1 immunotherapy combined with chemotherapy,including 35 patients treated with Camrelizumab and 25 patients treated with Sintilimab.All patients can evaluate the curative effect.The short-term efficacy of overall PD-1 combined immunotherapy:CR 0 case(0/60,0%),PR 32 cases(32/60,53.4%),SD 20cases(20/60,33.3%),PD 8 cases(8/60,13.3%),ORR 53.3% and DCR 86.7%.The short-term efficacy of different ICIs combined chemotherapy was analyzed respectively.In the Camrelizumab group: CR0 case(0/35,0%),PR 19 cases(19/35,54.3%),SD 11 cases(11/35,31.4%),PD 5 cases(5/35,14.3%),ORR 54.3% and DCR 85.7%.In the Sintilimab group: CR 0 case(0/25,0%),PR 13cases(13/25,52.0%),SD 9 cases(9/25,36.0%),PD 3 cases(3/25,12.0%),ORR 52.0% and DCR88.0%.There was no significant difference in short-term efficacy between the two groups(P>0.05).The results of long-term survival analysis of advanced ESCC showed that the m OS and m PFS of total first-line immunotherapy were 18.2(9.2-28.9)months and 8.1(5.1-14.8)months respectively.The survival time of patients treated with different ICIs combination therapy was analyzed.The m OS and m PFS of the patients in the Camrelizumab group were 18.1(9.2-28.1)months and 8.2(5.2-14.6)months respectively,and the m OS and m PFS of the patients in the Sintilimab group were 18.5(9.7-28.9)months and 7.8(5.1-14.8)months respectively.There was no significant difference in long-term effect(m OS and m PFS)between the two groups(P> 0.05).The results of Cox proportional hazard regression analysis suggested that the expression of PD-L1 may be an independent prognostic factor for OS and PFS in advanced ESCC patients who received first-line PD-1 checkpoint inhibitors(Camrelizumab or Sintilimab)combined with chemotherapy(P<0.05).Part II: differential expression analysis of TCGA database in patients with advanced ESCC showed that the expression of ECRG4 was down-regulated in ESCC tumor tissues.The results of ECRG4 and ESCC tumor immune micro environment analysis showed that ECRG4 expression was low in ESCC tumor tissue,and ESCC tumor immune microenvironment was in a state of immunosuppression.The results of ECRG4 and immune cell infiltration analysis showed that ECRG4 was positively correlate d with CD8+T cells,M1 macrophages,follicular helper T cells and resting mast cells,while ECRG4 was negatively correlated with M0 macrophages,activated chemical mast cells,eosinophils and activated dendritic cells.179 genes differentially expressed with ECRG4 gene were identified by differential gene expression identification.Through coexpression analysis,it was found that ECRG4 was positively correlated with ATP1A2,LDB3,CASQ2,PYGM,AC005180.2 and PGM5,and negatively correlated with FAM136 A,RAD51,KNSTRN and other genes.The results of GO and KEGG enrichment analysis and GSEA enrichment analysis show that ECRG4 may regulate the immune effect of immune cells in ESCC tumor immune microenvironment through molecular mechanisms such as energy metabolism and signal transduction,suggesting the potential molecular mechanism of ECRG4 affecting ESCC tumor immune microenvironment.The results of correlation analysis between ECRG4 and immune checkpoint genes showed that the expression of ECRG4 was significantly correlated with immune checkpoint genes PD-1,CTLA-4,LAG3,PD-L2,PD-L1,TIGIT,HAVCR2 etc,suggesting that immune effects of immune cells in tumor immune microenvironment of ESCC were regulated.ESCC survival analysis of TCGA database showed that the expr ession of ECRG4 was significantly correlated with OS and PFS in patients with ESCC.The difference is statistically significant(P < 0.05).The clinical features,TNM stage,pathological grade and ECRG4 gene expression were used to establish a line chart to pr edict the 1,3 and 5 year survival rates of patients with ESCC.A model for predicting clinical treatment and prognosis of ESCC was successfully constructed.Conclusion:1.The results of retrospective analysis showed that the real world of advanced ESCC first-line PD-1 checkpoint inhibitors(Camrelizumab or Sintilimab)combined with chemotherapy was effective.There was no difference in efficacy between Camrelizumab and Sintilimab.PD-L1 expression status may be an independent prognostic factor for OS and PF S in advanced ESCC patients who received first-line PD-1 checkpoint inhibitors(Camrelizumab or Sintilimab)combined with chemotherapy.2.PD-1 checkpoint inhibitors play an important role in the immunotherapy of advanced ESCC.The results of bioinformatics analysis suggest that the expression of ECRG4 affects the infiltration of immune cells in ESCC tumor immune microenvironment and the expression level of immune checkpoint genes such as PD-1 and PD-L1.ECRG4 can be used as a potential candidat e biomarker for predicting the efficacy of PD-1 immunotherapy in advanced ESCC. |
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