Comprehensive Genomic Analysis of the Prognostic and Immunological Characteristics of Tertiary Lymphoid structures and CD8+ T-cells in Pancreatic Ductal Adenocarcinoma

Abstract

Abstract Background Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is associated with poor prognosis. Previous publications have indicated tertiary lymphoid structure (TLSs) and CD8 + T-cells as prognostic indicators for PDAC, and a positive correlation between CD8 + T-cell infiltration and TLSs was also observed in PDAC. However, different states of TLSs infiltration occurs, and not all stages of TLSs maturation are correlated with a high abundance of CD8 + T-cells in the tumor microenvironment (TME), also CD8 + T-cell infiltration could be influenced by other factors, thus an integrative characterization of the TLSs and CD8 + T-cells is urgently needed. Herein, we aimed to establish a novel scoring system for evaluating the risk for PDAC based on TLSs- and CD8 + T-cells-related genes.Methods In this study, we analyzed single-cell sequence (scRNA-seq) data from PDAC patients in GSA: CRA001160 cohort, which indicated the positive relationship between TLSs presence and CD8 + T-cell infiltration. TCGA-PAAD was used as the training cohort. ICGC-CA, E-MTAB-6134, and the joint cohort of GSE71729 and GSE85916 were used for validation. Using bioinformatics and machine algorithms, we established and validated a scoring method (T-C score) based on survival related genes highly expressed in TLSs and CD8 + T-cells in PDAC, which was then used to stratify patients into the low- and high- T-C score groups. Following that, we analyzed the differences in survival, pathway enrichment, mutation status, immune cell infiltration, expression of immune checkpoint associated genes, tumor stemness, and response to anti-tumor therapy between the two groups.Results The overall survival differed significantly between the low- and high- T-C score groups throughout the training and validation cohort. Good accuracy of the T-C score in predicting 1-, 2-, 3-, 4-, and 5-year survival was further confirmed in the training and validation cohort, respectively. Furthermore, the low T-C score group was correlated with lower tumor mutation burden (TMB), and lower levels of tumor stemness, compared to the high T-C score group, Besides, analysis using the TIDE web tool has verified that patients with lower T-C score exhibited advantages in immunotherapeutic responses. Patients with lower T-C scores might be more sensitive to the chemotherapeutic regimen and multi-kinase inhibitors. Collectively, the T-C score based on the TLSs- and CD8 + T-cells-related gene signature could serve as an effective model for predicting the survival and therapeutic responses of PDAC patients.