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Feun et al. Immunotherapy for hepatocellular carcinoma

mediated by enhancing interleukin (IL)-6 and tumor and indoleamine 2,3-dioxygenase (IDO) production. [13]
necrosis factor (TNF) expression. With increasing Unexpectedly, it was found that these dendritic cells
incidence of obesity in the western countries, NASH expressed high levels of cytotoxic T-lymphocyte
will become a greater risk factor for HCC. antigen-4 (CTLA-4) and PD-1. CTLA-4 was discovered
to be essential for IL-10 and IDO production. This
Another supporting factor is that spontaneous finding represents a target for immunotherapy as well
[1]
regression have been reported in HCC. Spontaneous as one possible explanation for immune tolerance.
regression has been reported in other cancers as well
and is thought to be mediated by immune response Human HCC tumor-infiltrating CD4+ CD69+ T regs
in the host. Although infrequent, these occurrences are higher than conventional CD4+ CD25+ Foxp3+ T
suggest it may be possible to enhance the immune regs and correlates with tumor progression. [14] These
system against certain malignancies. T regs do not express CD25 or Foxp3 but express
high levels of mouse transforming growth factor beta
In addition, more than 50% HCC patients develop 1 (mTGF-β1), PD-1, CTLA-4 and could suppress CD4
spontaneous cellular or humoral immune response T-cell proliferation via mTGF-β1. [14] The percentage
against NY-ESO-1. Furthermore, tumor-associated of these T regs in tumors correlated significantly with
[2]
antigens (TAA)-specific CD8+ T-cell immune responses tumor progression.
have been described [most studied include AFP,
glypican-3, NY-ESO-1, SSX-2, MAGE-A, human Failure of HCC-associated antigen production
[3]
telomerase-reverse transcriptase (h-TERT)]. More presentation by antigen presenting cells is due to
than 50% HCC patients had HCC-infiltrating TAA- decreased expression of HLA class 1 molecules and
specific CD8+ T-cells and these cell numbers ineffective antigen processing. [15,16]
correlated with progression-free survival. [4]
Increase in T regulatory cells, invariant NK T-cells,
In HCC, the number of T regulatory cells increased both MDSC and tumor-associated macrophages may play
[5]
in peripheral blood and inside tumor itself. Intratumoral a role and a decrease in CD4+ T helper cells has
T regs correlated with disease progression and poor been reported. [4,11,17-20]
prognosis. Activation of T-cell infiltration (CD4+,
[6]
CD8+, natural killer cells) has been observed after There is an increase in CD4+, CD25+ T regs
liver ablation. [7,8] Together the data shows that within tumor infiltrating lymphocytes (TILs) which is
inflammation is a common feature seen in HCC and associated with decrease in number and function of
this tumor can elicit an immune response. CD8+ T-cells. [5,17]

REASONS FOR HCC IMMUNE TOLERANCE T-cell (CD4+) exhaustion and apoptosis have
been associated with chronic HCV infection. [21]
If HCC is typically an inflammation-associated cancer The CD4+ T-cells of chronic HCV-infected patients
and can be immunogenic, why is there immune displayed increased surface expression of TRAIL and
tolerance? There are several factors which may be expression of other immune exhaustion molecules.
involved. In addition, indoleamine 2,3-dioxygenase activity in
increased and IDO is a T-cell proliferation-limiting
On a cellular level, the liver is a site for myeloid- enzyme. Other molecules associated with T-cell
derived suppressor cells (MDSC) which can inhibit exhaustion and apoptosis signaling in peripheral
effector T-cell function and decrease natural killer blood mononucleocytes from chronically infected HCV
(NK) cell cytotoxicity and cytokine production. The patients have been described. [21]
frequency of MDSCs correlates with progression-free
[9]
survival in HCC after radiofrequency ablation. It has LAG-3 expression has been found to be significantly
been suggested that MDSCs interact with Kupffer cells up-regulated in tumor infiltrating CD8+ T-cells in HCC
to induce programmed death-1 (PD-1) expression patients and a severe functional defect was detected
and MDSCs may help expand T regs. [10] Depletion of in tumor infiltrating HBV-specific CD8+ T-cells at the
T regs or MDSCs may prompt spontaneous immune tumor site. [22] Because LAG-3 is an inhibitory molecule
responses against α-fetoprotein (AFP). [11,12] that helps to downregulate T-cell responses, there
was a correlation between LAG-3 expression and
A new subset of immune suppressive cells has been HBV-specific CD8+ T-cell dysfunction.
described in HCC called regulatory dendritic cells
(DCs) which can suppress T-cell activation via IL-10 Thus, the immunosuppression that is seen in HCC is
44 Hepatoma Research ¦ Volume 3 ¦ March 22, 2017