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Figure 3. Liver immune microenvironment and tumor growth. A: immune attack on circulating tumor cells. Circulating tumor cells entering the sinusoidal area are attacked by immune cells in the sinusoid, especially Kupffer cells and NK cells. These cells eliminate tumor cells via phagocytosis, cytotoxic granules, death-receptor pathways, nitric oxide, or ROS; B: extravasation of tumor cells into the hepatic parenchyma. Following firm attachment to LSEC via adhesion molecules such as E-selection, VCAM-1, and ICAM-1, tumor cells escape from the sinusoidal space and invade into the extrasinusoidal space, which is rich in various growth factors such as HGF and IGF-1; C: remodeling of hepatic parenchyma and angiogenic sprouting. Tumor cell invasion into the extrasinusoidal space triggers HSC and M2 macrophage recruitment into the tumors and increases production of collagen in and around hepatic metastases. HSC recruited into the metastases as myofibroblasts release growth factors, cytokines, and MMPs. IL-8 produced by HSC induces the expression of VEGFR2 and VEGF on endothelial cells and mediates autocrine and paracrine stimulation of vascular endothelium; D: rapid growth of hepatic metastasis. Vascular endothelial cells are further recruited to the tumor site and tumors become further vascularized. The vascularization of tumor results in rapid growth of metastasis. Local production of Th-2 type cytokines, deprivation of tryptophan, and elimination of activated T cells via PD-L/PD-L1 interaction result in non-T cell inflamed immune microenvironment in the hepatic metastasis. CXCR9: chemokine (C-X-C motif) ligand 9; CXCR10: chemokine (C-X-C motif) ligand 10; CCR5: C-C chemokine receptor 5; Fas L: fas ligand; HSC: hepatic stellate cell; HGF: hepatocyte growth factor; IL-6: interleukin 6; IL-8: interleukin 8; IL-10: interleukin 10; IFN-γ: interferon gamma; IGF-1: insulin growth factor-1; KC: kupffer cell; LSEC: liver sinusoidal endothelial cell; NO: nitric oxide; PD 1: programmed death 1; PD-L1: programmed death ligand 1; TDO: tryptophan 2,3 dioxtgenase; TGF-β: transforming growth factor beta; T reg: regulatory t Cell; VCAM-1: vascular cell adhesion protein 1; VEGF: vascular endothelial growth factor; VLA-4: very late antigen 4; ROS: reactive oxygen species