Exploring the effect of canine cancer-associated fibroblasts on T cell dynamics through the CXCL12/CXCR4 axis modulated by TGF-β1

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that modulate T cell immunity by secreting humoral factors and forming structural barriers. CAFs secrete the chemokine C-X-C motif chemokine ligand 12 (CXCL12), which binds to C-X-C chemokine receptor 4 (CXCR4) on T cells and induces chemotaxis. Transforming growth factor beta 1 (TGF-β1), another CAF-derived humoral factor, is believed to regulate the CXCL12/CXCR4 axis; however, a direct association between them has not been demonstrated in human medicine or veterinary medicine. This study investigated the role of canine CAFs in T cell migration via the CXCL12/CXCR4 axis and the regulatory influence of TGF-β1. CXCL12 and CXCR4 were expressed in the tumor stroma and on T cells, respectively, in dogs with epithelial malignant tumors. Canine CAFs secreted higher levels of CXCL12 and TGF-β1 than normal fibroblasts, and CAF-derived TGF-β1 modulated both CXCL12 secretion by CAFs and CXCR4 expression on T cells. Furthermore, canine CAFs induced T cell migration through the CXCL12/CXCR4 axis. These findings indicate that CAFs regulate T cell migration via the CXCL12/CXCR4 axis under TGF-β1 signaling, highlighting their critical role within the TME.