Heterogeneity of Cancer-Associated Fibroblasts and the Tumor Immune Microenvironment in Pancreatic Cancer

SIMPLE SUMMARY: Stroma-targeting therapy in pancreatic ductal adenocarcinoma (PDAC) has been extensively investigated, but no candidates have shown efficacy at the clinical trial stage. Studies of cancer-associated fibroblast (CAF) depletion in a mouse model suggested that CAFs have not only tumor-promoting function but also tumor-suppressive activity. Recently, single-cell RNA sequencing (scRNA-seq) has revealed the complex tumor microenvironment within PDAC, and subpopulations of functionally distinct CAFs and their association with tumor immunity have been reported. However, the existence of tumor suppressive CAFs and CAFs involved in the maintenance of PDAC differentiation has also been reported. In the future, therapeutic strategies should be developed considering these CAF subpopulations, with the hope of improving the prognosis of PDAC. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 9%. Cancer-associated fibroblasts (CAFs) have historically been considered tumor-promoting. However, multiple studies reporting that suppression of CAFs in PDAC mouse models resulted in more aggressive tumors and worse prognosis have suggested the existence of a tumor-suppressive population within CAFs, leading to further research on heterogeneity within CAFs. In recent years, the benefits of cancer immunotherapy have been reported in various carcinomas. Unfortunately, the efficacy of immunotherapies in PDAC has been limited, and the CAF-driven cancer immunosuppressive microenvironment has been suggested as the cause. Thus, clarification of heterogeneity within the tumor microenvironment, including CAFs and tumor immunity, is urgently needed to establish effective therapeutic strategies for PDAC. In this review, we report the latest findings on the heterogeneity of CAFs and the functions of each major CAF subtype, which have been revealed by single-cell RNA sequencing in recent years. We also describe reports of tumor-suppressive CAF subtypes and the existence of CAFs that maintain a differentiated PDAC phenotype and review the potential for targeted therapy.