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Terai et al. The liver and metastatic uveal melanoma

important determinant of clinical course and survival. immune cells occurs more frequently in epithelioid-cell-
After development of hepatic metastasis, the median type UM. An increased number of macrophages were
survival of patients is reported to be 6 to 12 months . associated with epithelioid tumor cells (P = 0.025),
[2]
heavy pigmentation (P = 0.001), and high microvascular
The liver copes with the bacterial pathogens, toxins, and density (P = 0.001). The 10-year melanoma-specific
food antigens transported through the portal vein from mortality rate increased with increasing numbers of
the gastrointestinal tract. The immune cells in the liver macrophages (0.10 for low vs. 0.57 for high numbers,
serve diverse functions ranging from immunity against P = 0.0012) . It has been reported that Treg cells are
[9]
bacteria and tolerance to food antigens. recruited into tumors by chemokines, CCL17 and CCL22
that are produced by M2 macrophages. Furthermore,
Circulating tumor cells (CTCs) that enter the liver tumor-produced CCL2 and CCL22 have a role not only
encounter a unique immune system. Interaction between in attracting tumor-promoting macrophages, but also in
the liver immune system and cancer cells provide a promoting their survival and M2 polarization .
[7]
complex tumor microenvironment. Newly developed
immunological treatment strategies such as immune While UM cells possess tumor-associated antigens
checkpoint blockade have appreciably improved the and tumor-infiltrating CD4 and CD8 cells are present
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survival of non-hepatic metastatic cutaneous melanoma in the primary UM, Treg cells are also present in the
patients; however, response of hepatic metastases tumor. One study has identified that the frequency
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is less robust. Likewise, UM patients with hepatic of CD4 , forkhead box P3 (FoxP3) Treg cells within
metastases have not derived meaningful survival benefit primary UM is correlated with the development of
from these immunetherapies. systemic metastasis [10] . The presence of Treg cells and
cyclooxygenase-2 expression in the tumors is especially
In this review article, we first overview the immune correlated with poor prognosis [10] . In terms of the role of
microenvironment of primary UM and that of the liver. NK cells in primary UM, down-regulation of HLA class I,
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We then summarize ongoing immunotherapies against which is a common mechanism for evading CD8 cells,
metastatic UM and discuss possible approaches renders tumors more susceptible to NK cell-mediated
to improve the efficacy of immunotherapy against lysis. However, while the NKG2D ligands (MIC-A and
metastatic UM. B) are expressed by 50% of primary UM, none of the
metastases express these ligands, indicating that
[11]
IMMUNOLOGICAL MICROENVIRONMENT metastatic UM might not be controlled by NK cells .
OF PRIMARY UVEAL MELANOMA The mechanism of inflammatory cell infiltration to

the primary UM and the reason for contradictory
The eye is considered an immune-privileged clinical outcomes remains speculative. Accumulative
organ. It has a unique ability to defend against evidence indicates that tumor-microenvironment
uncontrolled inflammation that could damage sight. crosstalk facilitates cancer cells to modulate the
Anatomical constraints to the development of an inflammatory response. Cancer cells interact with
immune response in the eye include the absence both the innate and the adaptive immune systems
of lymphatics that limit the traffic of immune cells to and skew the acquired T cell response from the T
the eye. Immune cells that enter the eye encounter helper 1 (TH1) type to the TH2 type. Cancer cells
immunosuppressive factors such as transforming also skew the phenotype of macrophages and
growth factor beta (TGF-β), α-melanocyte stimulating neutrophils to a type 2 differentiation and attract
hormone (MSH), retinoic acid (RA), and indoleamine myeloid-derived suppressor cells (MDSCs) as well
2, 3-dioxygenase (IDO) . These factors suppress as Treg cells to tumor sites [12] . UM cells may utilize
[6]
T cell proliferation and effector function, and could these immune cells for their survival and protection
induce immunosuppressive regulatory T (Treg) cells. from immunological attack. It is possible that UM cells
already induced tolerance against them when they left
A lymphocyte-rich tumor microenvironment generally from the eye. Immuno-modulatory microenvironment
indicates a good prognosis in various types of cancer. in the liver could further protect escaped UM cells
Paradoxically, in UM high densities of immune cells are from systemic immune surveillance.
associated with poor prognostic factors. Primary UMs
with monosomy 3, in comparison to those with disomy
3, are associated with a more vigorous inflammatory MECHANISMS OF METASTASIS TO THE
response, with infiltration by a variety of immune LIVER
cells, including CD8 , CD4 , CD3 CD8 Foxp3 T cells
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and CD68 CD163 M2 macrophages [7,8] . Infiltration of The mechanisms for development of metastases in
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232 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017