The cancer-associated fibroblast-related signature predicts prognosis and indicates immune microenvironment infiltration in gastric cancer.

Background: Gastric cancer (GC) is one of the most common cancers, with a wide range of symptoms and outcomes. Cancer-associated fibroblasts (CAFs) are newly identified in the tumor microenvironment (TME) and associated with GC progression, prognosis, and treatment response. A novel CAF-associated prognostic model is urgently needed to improve treatment strategies.

Methods: The detailed data of GC samples were downloaded from The Cancer Genome Atlas (TCGA), GSE62254, GSE26253, and GSE84437 datasets, then obtained 18 unique CAF-related genes from the research papers. Eight hundred eight individuals with GC were classified as TCGA or GSE84437 using consensus clustering by the selected CAF-related genes. The difference between the two subtypes revealed in this study was utilized to create the "CAF-related signature score" (CAFS-score) prognostic model and validated with the Gene Expression Omnibus (GEO) database.

Results: We identified two CAF subtypes characterized by high and low CAFS-score in this study. GC patients in the low CAFS-score group had a better OS than those in the high CAFS-score group, and the cancer-related malignant pathways were more active in the high CAFS-score group, compared to the low CAFS-score group. We found that there was more early TNM stage in the low CAFS-score subgroup, while there was more advanced TNM stage in the high CAFS-score subgroup. The expression of TMB was significantly higher in the low CAFS-score subgroup than in the high CAFS-score subgroup. A low CAFS-score was linked to increased microsatellite instability-high (MSI-H), mutation load, and immunological activation. Furthermore, the CAFS-score was linked to the cancer stem cell (CSC) index as well as chemotherapeutic treatment sensitivity. The patients in the high CAFS-score subgroup had significantly higher proportions of monocytes, M2 macrophages, and resting mast cells, while plasma cells and follicular helper T cells were more abundant in the low-risk subgroup. The CAFS-score was also highly correlated with the sensitivity of chemotherapeutic drugs. The low CAFS-score group was more likely to have an immune response and respond to immunotherapy. We developed a nomogram to improve the CAFS-clinical score's usefulness.

Conclusion: The CAFS-score may have a significant role in the TME, clinicopathological characteristics, prognosis, CSC, MSI, and drug sensitivity, according to our investigation of CAFs in GC. We also analyzed the value of the CAFS-score in immune response and immunotherapy. This work provides a foundation for improving prognosis and responding to immunotherapy in patients with GC.