Characterization of aging-related profiles in esophageal cancer reveals a signature predicting favorable outcome and immunogenicity

Background: It has been revealed that aging plays crucial roles in tumorigenesis, prognosis, and therapy response of tumors including esophageal carcinoma (ESCA). In this work, we aim to establish an aging-relevant risk signature to assess the survival outcome and immunogenicity status of ESCA patients. Methods A total of 351 ESCA patients with both gene expression data and clinical information from 3 independent datasets were curated. The Lasso-Cox regression model was applied to identify the aging genes that contributed most to the survival outcome. The risk signature was constructed by combining the specific gene expression level with the corresponding regression coefficients. Microenvironment-based immunologic factors, mutational burden, and significantly mutated genes were evaluated based on the identified risk groups. One cohort under the immune checkpoint inhibitor (ICI) treatment was used to investigate the immunotherapy predictive roles of the determined aging signature. Results Based on the 22 aging-relevant genes, a risk signature was constructed. ESCA patients with low-risk scores had improved survival outcomes in both discovery and validation datasets. Subsequent immunologic exploration demonstrated that the enhanced infiltration abundance of immune-response cells, decreased abundance of immune-suppressive cells, immune response-related signals, and the preferable ICI indicator enrichment were found in the low-risk group. Genomic mutation analysis showed the elevated mutational burden and increased mutation rates of significantly mutated genes of TP53 , NAV3 , and FAT1 were observed in patients with low-risk scores. In the ICI-treated cohort, we noticed that low-risk aging scores were significantly linked to favorable treatment outcomes and elevated response rates. Conclusions In summary, our identified aging risk signature showed the associations with survival, immune microenvironment, immunogenicity, and especially, the immunotherapy efficacy, which offers the clues for guiding prognosis evaluation and immune treatment strategies, and promotes precision therapy of ESCA patients.