Role of immunotherapy in downsizing hepatocellular carcinoma prior to liver transplantation

Figure 1 Schematic representation of the major components of the tumor microenvironment in patients with hepatocellular carcinoma. The main elements of the TME can affect tumoral spread both positively and negatively. The migration of TAMs and TANs can enhance the antitumoral immune response (M1 and N1 subpopulations) through the production of inflammatory mediators, such as TNF-α, NO and IL-1β, whereas M2 and N2 subpopulations promote tumoral spread by producing immunosuppressive molecules and modulating T-cell function. The immune upregulating effects of NK cells and CTLs are typically blunted in patients with HCC due to the presence of factors secreted by components of the TME. MDSCs mute NK responses, increase levels of galectin-9, IL-10, TGF-β, and promote PD1-PDL1 interactions, favoring tumor spread. Treg cells, LSECs and KCs all promote HCC development by inducing CTL dysfunction, immune evasion, and expression of immune-downregulating factors. CCL2: Chemokine receptor type 2; CCL5: Chemokine receptor type 5; CCL7: Chemokine receptor type 7; CX3CL: Chemokine (C-X3-C motif) ligand 1; M-CSF: Macrophage colony stimulating factor; GM-CSF: Granulocyte macrophage colony stimulating factor; VEGF: Vascular endothelial growth factor; TAMs: Tumor associated macrophages; M1: Subpopulation 1 of TAMs; M2: subpopulation 2 of TAMs; IL-10: Interleukin 10; TGF-β: Transforming growth factor beta; TNF-a: Tumor necrosis factor alpha; NO: Nitric oxide; IL-1β: Interleukin 1 beta; TANs: tumor associated neutrophils; N1: Subpopulation 1 of tans; n2: subpopulation 2 of TANs; CD66b: Cluster of differentiation 66 type b; PDL1: Programmed cell death ligand 1; PD1: Programmed cell death receptor 1; CTL: Cytotoxic CD8+ T cells; Tregs: T regulatory cells; FasL: Fas ligand; IFN-γ: Interferon gamma; CXCL17: Chemokine (C-X-C motif) ligand 17; NK cells: Natural killer cells; MCP-1: Monocyte chemoattractant protein-1; HiF: Hypoxia inducible factor; HSCs: Hepatic stellate cells; MDSCs: Myeloid derived suppressor cells; CAFs: Cancer associated fibroblasts; FGF: Fibroblast growth factor; MMP2/9: Matrix metalloproteases 2 and 9; LSECs: Liver sinusoidal endothelial cells; KCs: Kupffer cells.