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Figure 1. Tumor- and stromal cell-mediated immunosuppressive interactions. Both tumor cells and the surrounding stromal cells heavily influence the tumor-specific cytotoxic immune cells via direct cell-cell contact and paracrine factors. Red arrows denote negative, or inhibiting, influences and green arrows positive, or activating, influences. (1) Tumor cells increase the expression levels of checkpoint molecules such as PD-L1 and FasL that attach to CTLs expressing PD-1 and Fas, respectively. Tumors may also escape detection altogether from attackers by modulating MHC and antigenic levels. (2) B7 ligands on APCs interact with CTLA-4 on T cells to inhibit the latter’s activities. (3) Tumor cells modify the TME by producing excess acidic metabolites, NOS, Arg1, and the immunosuppressive cytokines TGF-β and IL-4. (4) Likewise, the tumor stroma shares in these activities by producing similar factors as well as ROS, IL-10, and IL-17. (5) The sharing of growth factors and pro-tumor cytokines between tumor cells and stromal cells further amplifies the inhibitory effect on anti-tumor immune cells. (6) Depending on the mechanisms encountered, the anti-tumor immune cells can undergo multiple pathways of inhibition, including exhaustion, lack of tumor targeting, or apoptosis. Arg1: arginase 1; CAF: cancer-associated fibroblast; CTL: cytotoxic T lymphocyte (CD8+); CTLA-4: cytotoxic T-lymphocyte-associated protein 4; DC: dendritic cell; FasL: fas ligand; M1: M1 macrophage; M2: M2 macrophage; MDSC: myeloid-derived suppressor cell; MHC: major histocompatibility complex; NOS: nitric oxide synthase; NK: natural killer; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; ROS: reactive oxygen species; TGF-β: transforming growth factor-β; TME: tumor microenvironment; Treg: T regulatory cell; APCs: antigen presenting cells