Fig. 2.
The AngII/AT1R axis regulates the tumor stroma and contributes to an immunosuppressive microenvironment. AngII/AT1R signaling can increase production and release of several proinflammatory cytokines in both tumor and stromal cells. Immunomodulatory cytokines regulate a myriad of immunosuppressive immune responses by modulating differentiation, recruitment, and function of both myeloid and lymphoid immune cell types (4, 43, 44). More precisely, these cytokines suppress the differentiation and function of immunostimulatory cell types [for example, TH (T helper) and CD8+ cells, NK cells, and dendritic cells] and activate recruitment and function of tumor-promoting cell types [such as Tregs, TH17 cells, TANs, TAMs (tumor-associated macrophages), and MDSCs (myeloid-derived suppressor cells)]. Fibroblasts are a major source of cytokines and also play a key role in establishing a desmoplastic stroma by production and deposition of ECM. The dense tumor fibrosis represents a physical barrier to immune cell infiltration (45) and compresses blood vessels by increasing tissue stiffness and solid stress. The reduced tumor perfusion results in a hypoxic and acidic milieu, which further promotes immunosuppression (46–48). Vascular endothelial growth factor (VEGF)–induced vascular leakiness (48) and AngII-mediated vasoconstriction (76, 77, 80) further impair tumor perfusion and aggravate hypoxia. GM-CSF, granulocyte-macrophage colony-stimulating factor. PGE2, prostaglandin E2.