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Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2015.173 Figure 1 Inhibition of DC immunogenic functions by the HCC microenvironment Figure 1 | Inhibition of DC immunogenic functions by the HCC microenvironment. HCC cells express TAAs and neo-antigens arising from private driver or passenger gene mutations. Following capture of cell debris, DCs process and present tumour antigens to T cells. In the HCC microenvironment, TREG cells block the immunostimulatory functions of DCs through various mechanisms: CTLA-4, constitutively expressed on TREG cells and inducibly expressed on activated effector T cells, prevents CD28 binding to CD80/CD86, thus inhibiting priming and expansion of CD4+ and CD8+ lymphocytes. CTLA-4 also induces reverse CD80/CD86 signalling in DCs, leading to the induction of the immunosuppressant molecules IL-10 and IDO. Intratumour DCs express both PD-1 and PD-L1. PD-1–PD-L1 ligation induces the production of IL-10 and IDO by DCs. Hypoxia enhances the production of proangiogenic molecules including adenosine (generated from ATP by the hypoxia-induced ectonucleases CD39 and CD73), PDGF, VEGF and lactic acid. The latter stimulates TAMs to release arginase and VEGF. Adenosine and VEGF inhibit APC co-stimulatory functions and promote angiogenesis. Abbreviations: A2AAR, human adenosine receptor A2A; APC, antigen-presenting cell; ARG, arginase; CTLA-4, cytotoxic T-lymphocyte protein 4; CXCL12, stromal cell-derived factor α; CXCR4, CXC chemokine receptor type 4; DC, dendritic cell; FoxP3, forkhead box protein P3; HCC, hepatocellular carcinoma; HIF-1α, hypoxia-inducible factor-1 α; IDO, indoleamine 2,3-dioxygenase; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; PDGF, platelet-derived growth factor; TAA, tumour-associated antigen; TAM, tumour-associated macrophage; TCR, T-cell receptor; TGF-β, transforming growth factor β; TREG cell, regulatory T cell; VEGF, vascular endothelial growth factor. Prieto, J. et al. (2015) Immunological landscape and immunotherapy of hepatocellular carcinoma Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2015.173