Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2015.173 Figure 2 Inhibition of NK and T cell effector functions by the HCC microenvironment Figure 2 | Inhibition of NK and T cell effector functions by the HCC microenvironment. Upon antigen recognition, IFN-γ released by CD4+ and CD8+ T cells induces PD-L1 on both APCs and tumour cells. PD-1–PD-L1 interactions result in T-cell exhaustion and prevent tumour-cell killing. Besides PD-1–PD-L1, CTLA-4, TIM-3, LAG-3 and BTLA are other membrane-linked T-cell inhibitory molecules. Both HCC cells and TREG cells secrete and respond to the EGFR ligand amphiregulin, which stimulates HCC cell growth and TREG cell activity. Tumour cells release CXCL12, which attracts myeloid and lymphoid cells via CXCR4. MDSCs abrogate NK and T-cell activity via TGF- β and other mechanisms. Myeloid cells mediate immunosuppression by releasing ROS, TGF- β, IL-10, PGE2, MMPs and via the enzymatic actions of arginase and IDO. CAFs generate ECM and maintain inflammation by producing PGE2 and MMPs. Hypoxia induces PD-L1 in HCC and myeloid cells in the tumour microenvironment. In myeloid cells PD-1–PD-L1 gives rise to the release of IL-10, TGF-β and arginase. Adenosine acting via its receptor blocks CD4 and CD8 T cell effector functions and inhibits macrophage activation. IFN-γ stimulates TAMs to secrete galectin-9, which upon binding TIM-3 enhances TREG cell activity and promotes IL-6 secretion by TAMs, which in turn induces IL-10 production by MDSCs. Abbreviations: A2AAR, human adenosine receptor A2A; APC, antigen-presenting cell; BTLA, B and T lymphocyte attenuator; CAF, cancer-associated fibroblast; CTLA-4, cytotoxic T-lymphocyte protein 4; CXCL12, stromal cell-derived factor α; CXCR4, C-X-C chemokine receptor type 4; DC, dendritic cell; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; HCC, hepatocellular carcinoma; HVEM, herpesvirus entry mediator; IDO, indoleamine 2,3-dioxygenase; LAG-3, lymphocyte activation gene 3; NK, natural killer; MDSC, myeloid-derived suppressor cell; MMP, matrix metalloprotease; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; ROS, reactive oxygen species; TAA, tumour-associated antigen; TAM, tumour-associated macrophage; TCR, T-cell receptor; TGF-β, transforming growth factor β; TIM-3, T-cell immunoglobulin and mucin domain-containing protein-3; 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