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Terai et al. The liver and metastatic uveal melanoma
CD95/CD95L pathway. Cytokines and chemokines Recently, microscopic investigation on inflammatory
such as TNF-α, IL-8, and CXCL10 can activate resident cells in advanced metastatic uveal melanoma tissue
tumoricidal macrophages, as well as recruit host immune specimens was reported by Coupland’s group [49] . They
cells with anti-tumor activities [Figure 3A]. reported that CD3 T lymphocytes were noted both
[51]
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within tumor and surrounding tissues. Of note, CD8
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Growth phase T lymphocytes were “few” in number within metastatic
While an efficient first line defense can defeat some UM and were predominantly seen peritumorally at
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CTCs trapped in the liver, local inflammatory response the tumor/normal liver interface. In contrast, CD4 T
can also promote tumor cell adhesion to LSECs and lymphocytes showed a high perivascular density within
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subsequent trans-endothelial migration of tumor cells, melanoma. The characteristics of CD4 T cells were not
which results in escape from the cytotoxic resident further investigated; however, it is possible that these
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KCs and NK cells. IL-10 production from KC or LSECs CD4 T cells might be Treg cells recruited from the
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enhances the expression of the chemokine receptor peripheral circulation. Furthermore, CD68 and CD163
CCR5, but down-regulates CCR7 expression by DCs TAMs of “indeterminate” morphology were observed
thus preventing their homing to the secondary lymphoid in metastatic UM, suggesting the presence of the pro-
tissue [41] . E-selectin, VCAM-1, and ICAM-1 play tumorigenic M2 phenotype. It has also been reported
essential roles in tumor cell arrest and extravasation that tumor infiltrating T cells obtained from metastatic
into the hepatic parenchyma [52] . In particular, E-selectin UM were difficult to expand ex-vivo despite the lack of
facilitates diapedesis of tumor cells and subsequent PD-L1 expression in tumor tissues [54] . Lack of PD-L1
invasion into the hepatic parenchyma. Invasion of expression by metastatic UM cells and marginalization
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tumor cells into the extra-sinusoidal space triggers the of CD8 T cells suggests an impaired anti-tumor
recruitment of HSCs and macrophages into the tumors. immune response in metastatic UM.
These macrophages are polarized by IL-4 and IL-13 [38]
towards M2 type macrophages expressing arginase-1 [48] Grossniklaus et al. proposed two growth patterns
[Figure 3B]. Recruited HSCs release growth factors, of hepatic metastasis: “infiltrative” and “nodular”.
cytokines, and matrix metalloproteinases (MMPs), and They hypothesized that primary UM cells, expressing
increase production of collagen. As a result, recruitment high levels of c-Met and/or CXCR4, aggregate in
of vascular endothelial cells, assembly and turnover of the liver which contains HGF and CXCL12. These
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extracellular matrix, and proliferation tumor cells are metastatic UM cells have a CD133 tumor stem cell-like
promoted. Tumor cells also produce VEGF to promote phenotype, and give rise to the infiltrative or nodular
growth patterns depending on whether the tumor is
angiogenesis [47] [Figure 3C]. Hepatocytes contribute in the sinusoidal space (infiltrative) or periportal area
to fibrosis and neovascularization through secretion of (nodular). The infiltrative growth pattern showed
IGF-1 and IGF-2, factors that promote HSC recruitment cell growth within the sinusoidal space. The nodular
and activation. IGF-1 can also directly enhance tumor growth pattern predominantly contained nodules of
cell growth. tumor that effaced, rather than infiltrated, the adjacent
hepatocytes. Hepatic metastasis with infiltrative pattern
In addition to interacting with various residential showed the lack of VEGF protein in the tumor, but
cells in the liver, MDSCs are recruited to tumor sites tumor cells induce MMP9 expression in monocytes and
in response to mediators released by tumor and/or dissect through the tissue planes and creates “pseudo-
resident hepatic cells. There are two different types sinusoidal spaces”. On the other hand, UM cells that
of MDSC: polymorphonuclear MDSC (PMN-MDSC) metastasize to the periportal areas in the hepatic
and monocytic MDSC (M-MDSC). In the tumor sites, triadcoopt the portal venules for nutrition and hypoxia
M-MDSCs are more prominent than PMN-MDSC, resulting in MMP production and VEGF expression
and M-MDSC rapidly differentiate to tumor-associated for angiogenesis. The role of the immune system in
macrophage (TAM) to enhance tumor growth. CD68 / development of these two growth patterns needs to be
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CD163 TAMs are observed in metastatic UM in the further investigated.
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liver [49] . MDSCs produce immunosuppressive cytokines,
such as IL-10 and TGF-β, and induce Tregs [53] .
Subsequently, immunological equilibrium between CURRENT IMMUNOTHERAPIES FOR
tumor cells and host immune responses is shifted to METASTATIC UVEAL MELANOMA
the escape (growth) phase [Figure 3D]. More vascular
endothelial cells are subsequently recruited to the The major difference between CM and UM is the
tumor site and the tumors become further vascularized. low mutational burden in UM compared to the high
Eventually, the vascularization of tumor results in rapid mutational burden in CM [19] . Metastatic UM is highly
growth of metastasis. resistant to traditional systemic chemotherapies, and
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017 237