Page 13 - linda_borst
P. 13

A A                                                                  B B
                                                       m
                                                       u
                                                   d
                                                         m
                                                         r
                                                        o
                                                   o
                                                m
                                                y
                                               L Lymph node  e  T Tumor microenvironment  t
                                                  n
                                                 h
                                                 p
                                                              o
                                                              r
                                                             i
                                                               n
                                                                n
                                                                e
                                                               m
                                                           r
                                                           c
                                                          i
                                                           o
                                                             v
                                                            n
                                                            e
                                    l
                                                                       o
                                                                         h
                                                                     e
                                  T T cell  l                       E Effector phase
                                   c
                                                                     f
                                    e
                                                                        p
                                                                          e
                                                                       r
                                                                      t
                                                                          s
                                                                    f
                                                                         a
                                                                      c
                                  t
                                 a activation  n
                                  c
                                   i
                                     i
                                     o
                                    t
                                   v
                                    a
                                 T cell
                           APC        Activation &
                                      expansion
                                                                             Cancer cell
                                Priming signals                     Immune attack
                           B7              CD28               TCR              MHC
                                                                                                   Chapter 1
                          MHC              TCR               CTLA-4            B7
                                                              PD-1             PD-L1
                                                              TIM3             Galectin-9
                           B7              CTLA-4             TIGIT            CD155
                                                          CD94/NKG2A           HLA-E/Qa-1 b
                        i
                        g
                      A Antigen  n
                       n
                       t
                        e
                                                                                u
                                                                                m
                                                           t
                                                               e
                                                                                 r
                                                                                  c
                                                                                 o
                                                           c
                                                            a
                                                             t
                                                              T
                                                               c
                                                             d
                                                            i
                                                            v
                                                             e
                                                                                  e
                         n
                       s
                          g
                                            i
                          c
                         i
                         t
                        n
                        e
                                            a
                                              T
                                             e
                           e
                                               e
                                              c
                       r
                       e
                                             v
                      p presenting cell  l l  N Naive T cell  l l  A Activated T cell  l l  Inhibitory signals  T Tumor cell  l l
                Figure 1.

                Interaction  of  naïve  T  cells  during  activation  by  the  antigen  presenting  cell  (APC)  in  the  lymph  node  and  the





                expression of checkpoint inhibitors on the activated T cell upon interaction with the cancer cell in the suppressive




                tumor  microenvironment.  (A)  The  process  of  T  cell  activation  involves  antigen  presentation  by  the  major

                histocompatibility complex (MHC) molecules on the APCs to the corresponding T cell receptor (TCR) on naive


                T cells. The interaction of costimulatory molecules CD28 and B7 is required for full activation, which is tightly




                regulated by inhibitory checkpoints, like CTLA-4, to avoid collateral damage and autoimmunity . (B) In the tumor
                                                                              6
                microenvironment the cancer cell expresses ligands (e.g. B7, PD-L1, CD155, HLA-E) for inhibitory receptors present



                on the activated T cell to inhibit its effector function (e.g. PD-1, CTLA-4, TIM3, TIGIT, NKG2A). Figures 1 was created
                with BioRender.com.
                IMMUNE THERAPY OF CANCER

                Various  methods  of  immune  therapy  have  been  developed  to  reinvigorate  or  initiate


                immune  responses  against  tumors,  including  vaccination,  adoptive  transfer  of  immune



                cells and administration of monoclonal antibodies to specific tumor targets or inhibiting

                immune checkpoint receptors. Therapeutic vaccination serves to activate the naïve T cell






                repertoire  but  also  to  expand  and  reactivate  the  existing  tumor  specific  T  cell  pool 32,33 .


                Though vaccination shows increased frequencies and activation of tumor-specific T cells,


                the  success  of  vaccination  has  been  hampered,  predominantly  due  to  the  induction  of


                an  immune-suppressive  micromilieu  in  the  tumor  and  to  immune  escape  mechanism
                of cancer cells, e.g. the expression of immune checkpoint ligands. PD-L1 expression, for
                instance, can be induced by IFN-γ , which is expressed during an active anti-tumor immune


                                           34
                response.  This  has  been  referred  to  as  a  mechanism  of  adaptive  immune  resistance .

                                                                                        35
                Blockade of immune checkpoints using monoclonal antibodies, initially shown for CTLA-4,



                demonstrated tumor rejection, including preexisting tumors and resistance to a secondary





                exposure in pre-clinical mouse models , motivating the introduction of blocking antibodies
                                               36
                against CTLA-4 in the clinic. The CTLA-4 monoclonal antibody ipilimumab was the first FDA


                 GENERAL INTRODUCTION                                                   11
   8   9   10   11   12   13   14   15   16   17   18