Study On The Effect Of Microenvironment Changes On Prognosis And Immunotherapy In Esophageal Squamous Cell Carcinom

Esophageal squamous cell carcinoma(ESCC)is one of the most common and lethal malignant diseases.Therapy strategies provide only mild survival benefits for advantaged ESCC patients,with a 5-year survival rate of 20%-30%.In the past decade,immunotherapy has been widely studied and has exhibited potential in ESCC treatment.Immune checkpoint inhibitors such as monoclonal antibodies inhibiting programmed death 1(PD-1)or programmed death-ligand 1(PD-L1)have led to clinical benefits in ESCC.However,only a portion of ESCC patients have benefited from immunotherapy.The resistance of tumors to immunotherapy can be driven by tumor cell-intrinsic factors(e.g.,tumor mutation load and immune checkpoint inhibitor expression).Recent studies have also found that resistance can rely on changes in the tumor microenvironment.Different cell populations,such as tumor-infiltrating lymphocytes(TILs),tumor-associated macrophages(TAMs)and cancer-associated fibroblasts(CAFs),in the tumor microenvironment can play roles in cancer immunotherapy.We constructed a 12-gene immunotherapeutic response-related signature(IRRS)using the gene expression data of 274 ESCC patients based on significantly differentially expressed genes,which were compared between responders and nonresponders from various patient cohorts treated with immunotherapy.We systematically explored the potential importance of the IRRS as a predictive biomarker for prognosis.We explored the differences in both signaling pathways and mutations between the high-IRRS and low-IRRS score groups.The results indicated that the high score group may possess an immunosuppressive TME.We also explored the differences in the tumor microenvironment using single-cell RNA sequencing of 60 ESCC samples.We found that exhausted T(TEX)cells were enriched in the high-IRRS score groups and may cause immunosuppression in the TME.In addition,fibroblasts promote ECM remodeling,and ligands induce immunologic tolerance in the high-IRRS score group.Moreover,TAMs in low-IRRS score groups are sensitive to microenvironmental cues.We used human spatial transcriptomic and a mouse model mimicking human ESCC development to further explore the tumor microenvironment of high-and low-scoring patients.Three immunotherapy cohorts were used to verify the value of the IRRS in predicting immunotherapy response.The results proposed that patients with low IRRS scores may benefit from immunotherapy.In summary,in the present study,we established a novel survival prediction model,IRRS,by immunotherapy response genes in ESCC.We also used scRNA-seq as a reference to characterize cell types within the TME.Moreover,several immunotherapy cohorts were chosen to verify the efficacy of the IRRS score in predicting immunotherapy response.This study not only provides predictive biomarkers but also provides a new paradigm.