Cancer-associated fibroblast-related prognostic signature predicts prognosis and immunotherapy response in pancreatic adenocarcinoma based on single-cell and bulk RNA-sequencing

Cancer-associated fibroblasts (CAFs) influence many aspects of pancreatic adenocarcinoma (PAAD) carcinogenesis, including tumor cell proliferation, angiogenesis, invasion, and metastasis. A six-gene prognostic signature was constructed for PAAD based on the 189 CAF marker genes identified in single-cell RNA-sequencing data. Multivariate analyses showed that the risk score was independently prognostic for survival in the TCGA (P < 0.001) and ICGC (P = 0.004) cohorts. Tumor infiltration of CD8 T (P = 0.005) cells and naïve B cells (P = 0.001) was greater in the low-risk than in the high-risk group, with infiltration of these cells negatively correlated with risk score. Moreover, the TMB score was lower in the low-risk than in the high-risk group (P = 0.0051). Importantly, patients in low-risk group had better immunotherapy responses than in the high-risk group in an independent immunotherapy cohort (IMvigor210) (P = 0.039). The CAV1 and SOD3 were highly expressed in CAFs of PAAD tissues, which revealed by immunohistochemical staining. In summary, this comprehensive analysis resulted in the development of a novel prognostic signature, which was associated with immune cell infiltration, drug sensitivity, and TMB, and could predict the prognosis and immunotherapy response of patients with PAAD.