Integrating tertiary lymphoid structure–associated genes into computational models to evaluate prognostication and immune infiltration in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor response to all therapeutic modalities and dismal prognosis. The presence of tertiary lymphoid structures (TLSs) in various solid cancers is of crucial prognostic significance, highlighting the intricate interplay between the tumor microenvironment and immune cells aggregation. However, the extent to which TLSs and immune status affect PDAC prognosis remains incompletely understood. Here, we sought to unveil the unique properties of TLSs in PDAC by leveraging both single-cell and bulk transcriptomics, culminating in a risk model that predicts clinical outcomes. We used TLS scores based on a 12-gene (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13) and 9-gene (PTGDS, RBP5, EIF1AY, CETP, SKAP1, LAT, CCR6, CD1D, and CD79B) signature, respectively, and examined their distribution in cell clusters of single-cell data from PDAC samples. The markers involved in these clusters were selected to develop a prognostic model using The Cancer Genome Atlas Program database as the training cohort and Gene Expression Omnibus database as the validation cohort. Further, we compared the immune infiltration, drug sensitivity, and enriched and differentially expressed genes between the high- and low-risk groups in our model. Therefore, we established a risk model that has significant implications for the prognostic assessment of PADC patients with remarkable differences in immune infiltration and chemosensitivity between the low- and high-risk groups. This paradigm established by TLS-related cell marker genes provides a prognostic prediction and a panel of novel therapeutic targets for exploring potential immunotherapy.