Page 41 - Read Online

Terai et al. The liver and metastatic uveal melanoma

immunities. Following activation, NKT cells rapidly expressing PD-1 interact with PD-L1 on LSECs to
secrete either pro-inflammatory or anti-inflammatory become tolerogenic or apoptotic [42] . Activated T cells
cytokines and chemokines, and thereby determine the have been shown to be short-lived in the liver [29] .
direction for subsequent immunity or tolerance.
It is of note that tryptophan 2,3-dioxygenase (TDO)
Type I invariant NKT cells expressing specific T cell is predominantly expressed in the liver. In contrast,
receptors (TCRs) comprise 95% of liver NKT cells, while indoleamine 2,3-dioxygenase (IDO) is found in many
type II NKT cells expressing diverse TCRs make up tissues and induced by interferon (IFN)-γ. TDO and
less than 5% of them. NKT cells recognize non-peptide IDO are responsible for metabolism of tryptophan
antigen targets such as lipid and glycolipid components. (TRP).The metabolite of TRP, kynurenine (KYN),
They are activated by IL-12 or by interaction between binds to the aryl hydrocarbon receptor (AHR) on
NKG2D and its ligands on target cells. The role of NKT T cells to suppress their activity. Effector T cells
cells in cancer is rather controversial. In patients with are particularly sensitive to low TRP levels. Local
hepatocellular carcinoma (HCC), CD4 Vα24/Vβ11 depletion of TRP suppresses T cell proliferation
+
type I NKT cells secreting Th2 cytokines, accumulated and induces cell death [43] . AHR activation reportedly
in tumor sites, and inhibited tumor-specific CD8 T cell induces differentiation of Treg cells [44] .
+
responses [40] .
INTERACTIONS BETWEEN CTCS AND LIVER
T cells MICROENVIRONMENT
The normal resident lymphocytes of the human liver
consist of more CD8 T cells relative to CD4 T cells. CTCs can enter the liver through both the hepatic artery
+
+
Circulating T cells pass through the liver sinusoids and and portal vein. CTCs in the liver encounter various
can interact with KCs and LSECs. Antigens that are populations of residential cells that are specialized to
expressed in the liver might be taken up by immature carry out various immunological functions in the liver.
dendritic cells (DCs) and then presented to CD4 and Actual mechanism of establishment and progression of
+
CD8 T cells either in lymphoid-tissue aggregates in hepatic metastasis in UM are mostly speculative. Based
+
the portal tracts or in secondary lymphoid tissues. on the published literatures [13,29,30, 41,45-49] and our limited
Alternatively, antigens might be presented in situ by institutional experience, we propose the following two-
LSECs, KCs and, possiblyby hepatocytes. The outcome phase growth model for metastatic UM in the liver.
of antigen recognition by T cells in the liver could
induce the proliferation of T cells or activation-induced Microvascular phase
T-cell apoptosis. Antigen recognition could also result This phase starts with tumor cell arrest in the sinusoidal
in immune deviation to a suppressive or regulatory space. The final fate of surviving tumor cells can be
phenotype. determined by the interactions between tumor cells and
immune cells. These interactions can lead to tumor cell
The determination of outcome depends on death, or the growth of the tumor in the liver. Obstruction
upregulation and expression of an extensive panel of the sinusoidal vessels by clusters of CTCs can
of T-cell interacting molecules including intercellular result in transient blockade of blood flow and ischemia.
adhesion molecule 1 (ICAM1), MHC class II molecules, This could result in tumor cell destruction caused by
VCAM1, co-stimulatory molecules of the B7 family, and mechanical stress and deformation-associated trauma.
CD95 (FAS). These molecules might also modify cell Additionally, VCAM-1 expression on LSEC increases
trafficking, priming, and the induction of tolerance. and traps melanoma cells that enter the liver [50] . It was
reported that VCAM-1 expression on LSEC increased
In general, with the production of immune modulatory significantly within 24 h of melanoma cell entry into the
cytokines such as IL-10 and TGF-β, the antigen- liver [50] , and blocking VCAM-1 by antibodies decreased
presentation by LSECs and many DCs in the liver is microvascular retention of tumor cells and metastasis.
biased strongly towards the induction of CD4 T cells Tissue ischemia induces the local release of NO and
+
with a regulatory phenotype [41] , whereas both CD8 T reactive oxygen species, and kills tumor cells.
+
cells that are activated systemically and naive CD8
+
T cells that first encounter antigen in the liver are LSEC and KCs are likely to be the first resident cells
predisposed to undergo apoptosis. The liver sequesters that CTCs encounter in the liver. The tumor cells can be
activated T cells in an antigen-independent manner, eliminated by local, tumoricidal KCs. KCs can also activate
and the high apoptotic rate of such cells has given other innate immune response cells such as NK cells, NKT
rise to the idea that the liver might be a “graveyard” cells, and neutrophils. NK cells can mediate antitumor
for systemic T cells. Activated antigen-specific T cells cytotoxicity by secreting perforin/granzyme or through
236 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017