Figure 2.
Immunosuppressive mechanisms of the TME. Treg (regulatory T-) cells generate IL-10 and TGF-β angiogenic cytokines to suppress CTL (cytotoxic T-lymphocyte) activity. Myeloid-derived suppressor cells (MDSCs) produce reactive oxygen species (ROS), arginase (ARG) and nitric oxide (NO) that inhibit T-cell activation. Tumor-associated macrophages (TAMs) similarly block CTL and natural killer (NK) T-cells, immature dendritic cells cause T-cell anergy via IDO enzyme secretion, while cancer-associated fibroblasts (CAFs) and endothelial cells (tumor, lymphatic, and vascular) produce TGF-β and stimulate T-cell apoptosis by FasL-Fas binding (5, 6). MHC I is downregulated in tumor cells to inhibit T-cell recognition. FasL is expressed by tumors, killing T-cells (7). Tumors secrete VEGF to sustain tumor endothelial cells, and lactate and FGF to promote CAF development (8). Immunosuppressive TAMs are maintained by a suite of tumor secretions: CCL2, CXCL12, and IL-1β (8). NK cell inhibition by tumors is accomplished by release of IL6/10, IDO, and TGF-β. CAFs suppress NK cells via cytokines and growth factors including PGE2, TGF-β, and IDO (6). Tumors recruit immunosuppressive to the TME via TNF-α and CCL2 (9). IDO, indoleamine 2,3-dioxygenase; CD80, cluster of differentiation 80; M-CSF, macrophage colony-stimulating factor; CCL2, chemokine ligand 2; PGE2, prostaglandin E2; CXCL2, chemokine (C-X-C motif) ligand 2; TGF, transforming growth factor; IL, interleukin. Figure created by combining information from Jeanbart and Swartz (5), Hargadon et al. (10), Derbal et al. (8), Hasmim et al. (6), and Baginska et al. (9). See Abbreviations list for further definitions.