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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
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