Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines.

Abstract

Simple SummaryDespite advances in therapeutic modalities, the five-year overall survival for pancreatic cancer is still less than 10%. Pancreatic tumors are characterized by a highly fibrotic stroma comprised of activated cancer-associated fibroblasts (CAFs) which surrounds the cancer cells. Pancreatic CAFs are involved in creating an immunosuppressive tumor microenvironment by secretion of immunoregulatory and chemoattractive factors, which prevent tumor-reactive T-cell responses. This review article discusses recent discoveries about the role of different subsets of CAFs as regulators of anti-tumor immunity in pancreatic cancer, with emphasis on chemokines and suppressive factors. Understanding the interactions between T cells and CAFs as well as their spatial distribution within the tumor is of great importance for the development of novel targeted therapies to overcome immunosuppression and to enhance immunotherapy.Less than 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive 5 years or more, making it one of the most fatal cancers. Accumulation of T cells in pancreatic tumors is associated with better prognosis, but immunotherapies to enhance the anti-tumor activity of infiltrating T cells are failing in this devastating disease. Pancreatic tumors are characterized by a desmoplastic stroma, which mainly consists of activated cancer-associated fibroblasts (CAFs). Pancreatic CAFs have emerged as important regulators of the tumor microenvironment by contributing to immune evasion through the release of chemokines, cytokines, and growth factors, which alters T-cell migration, differentiation and cytotoxic activity. However, recent discoveries have also revealed that subsets of CAFs with diverse functions can either restrain or promote tumor progression. Here, we discuss our current knowledge about the interactions between CAFs and T cells in PDAC and summarize different therapy strategies targeting the CAF–T cell axis with focus on CAF-derived soluble immunosuppressive factors and chemokines. Identifying the functions of different CAF subsets and understanding their roles in T-cell trafficking within the tumor may be fundamental for the development of an effective combinational treatment for PDAC.