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often seen in tumor cells to avoid recognition. Defects at different layers of the MHC class I
                processing machinery are found. For example, mutations or loss of LMP-2 and -7, subunits
                 In 1891 Dr William Coley, often referred to as the “Father of Immunotherapy”, was the first
                of the multicatalytic proteasome complex generating peptide fragments, TAP1 and TAP2
                transporting these peptides into the endoplasmic reticulum (ER) , β2-microglobulin (β2m)
                 to search for a method to activate the immune system as an alternative treatment method
                stabilizing the MHC heavy chain were described. Although reduced MHC expression results
                 for sarcoma, after witnessing the painful death of an 18-year-old patient. For this, he used
                in reduced susceptibility to cytotoxic T cells, the vulnerability to NK cell lysis increases, as
                 a mixture of live and inactivated Streptococcus pyogenes and Serratia marcescens , leading
                NK cells rely on a balance of triggering and inhibitory signals, where MHC class I molecule
                 to curative effects. However, the clinical responses were not consistent and the attention
                induce an inhibitory signal through the engagement of inhibitory receptors .
                 soon diverted to the overwhelming developments in other types of therapies that later the
                 standard  of  care,  like  surgery,  radiotherapy  and  chemotherapy.  In  1909,  Paul  Ehrlich
                A second category of immune escape mechanism is the ability of cancer cells to express
                 developed a hypothesis that the development of tumors may be controlled by the immune
                ligands  of  inhibitory  receptor,  immune  checkpoint  (IC)  molecules,  on  their  cell  surface
                                                                               who proposed
                         . This hypothesis was further developed by Thomas and Burnet
                (Figure 1B). Asides from NK cells, many T cells also express inhibitory receptors. In the 1980’s
                 the theory of cancer immunosurveillance in 1957. They suggested that lymphocytes act as
                CTLA-4 was discovered on activated effector T cells and regulatory T cells (T ) . CTLA-4
                 guards and are responsible for recognizing and eliminating newly arising tumor cells that
                competes with costimulatory receptor CD28 for B7 ligands  and inhibits proliferation and
                 differ  from  normal  host  cells  by  their  expression  of  tumor  specific  neo-antigens  as  a
                IL-2 secretion by T cells by inhibiting T cell receptor (TCR) signal transduction via CTLA-4–
                 consequence  of  mutations.  However,  during  the  development  of  cancer,  a
                                                                                    26 process
                associated  tyrosine  phosphatase,  SHP-2,  resulting  in  dephosphorylation  of  TCR-ζ .  PD-1
                 comprising sustained proliferation, evasion of growth suppressors, cell death resistance,
                is another inhibitory receptor and was cloned in 1992 . Activation of the PD-1 gene was
                suggested to be involved in apoptotic cell death induced on lymphocytes. The ligand of
                 replicative immortality, angiogenesis, metastasis and reprogrammed metabolism , tumor
                PD-1 (PD-L1) is a member of the B7 gene family. PD-L1 is expressed by antigen presenting
                 cells finally manage to evade immune destruction . The process that leads to the evasion
                cells (APCs), but also on nonlymphoid tissues like heart and lung tissue. As mice deficient
                 of immune elimination is later described as immunoediting, because this includes all phases
                in PD-1 expression demonstrate autoimmunity , the interaction between PD-L1 and PD-1
                 of interaction between cancer and immune system beyond immunosurveillance .
                determines a threshold for peripheral tolerance, autoimmunity and the extend of immune
                responses  at  the  site  of  inflammation  in  balance  to  the  costimulation  of  CD28  by  B7 .
                By the expression of PD-L1, cancer cells embark on this natural tolerance threshold and
                jeopardize immune attack. There are also tumor extrinsic mechanisms, including preventing
                 The immunoediting hypothesis is composed of three phases: elimination, equilibrium and
                the infiltration of leukocytes, attracting immune suppressive cells and release of abundant
                 escape . This theory originates from microevolution in which the immune system selects
                immunosuppressive  cytokines 30,31 .  Together,  these  escape  mechanisms  lead  to  the  last
                phase of immunoediting, which is the escape of tumor cells from immune control, ultimately
                 for tumor cells that are best adapted and thereby the least immunogenic . During the first
                resulting in clinically detectable tumor lesions.
                 phase, the elimination phase, newly arising tumor cells are immunologically distinguishable
                 from normal cells by NK, CD4 and CD8 T cells by the expression of tumor specific neo-
                 Table 1. Classification of tumor-associated antigens 1-5
                Table 1. Classification of tumor-associated antigens 1-5
                  Tumor antigens          Examples
                  Differentiation antigens   Melan-A/MART-1, tyrosinase, gp-100, carcinoembryonic
                                          antigen (CEA), CD19 and NY-BR-1
                  Mutational antigens     abnormal forms of p53, β-catenin, CDK4
                  overexpressed/amplified   HER-2/neu, human telomerase reverse transcriptase
                  antigens                (hTERT), epidermal growth factor receptor (EGFR)
                  cancer-testis (CT) antigens  melanoma-associated antigen 3 (MAGE-A3), and NY-C0-58
                                          and NY-ESO-1
                  viral antigens          Human Papilloma Virus (HPV), Epstein Bar Virus (EBV) and
                                          Merkel cell polyomavirus (MCV)

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