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                In 1891 Dr William Coley, often referred to as the “Father of Immunotherapy”, was the first
                to search for a method to activate the immune system as an alternative treatment method
                for sarcoma, after witnessing the painful death of an 18-year-old patient. For this, he used a
                mixture of live and inactivated Streptococcus pyogenes and Serratia marcescens , leading
                to curative effects. However, the clinical responses were not consistent and the attention
                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
                developed a hypothesis that the development of tumors may be controlled by the immune
                system 9,10 . This hypothesis was further developed by Thomas and Burnet 11,12  who proposed   Chapter 1
                the theory of cancer immunosurveillance in 1957. They suggested that lymphocytes act
                as guards and are responsible  for recognizing  and eliminating newly arising tumor cells
                that differ from normal host cells by their expression of tumor specific neo-antigens as
                a  consequence  of  mutations.  However,  during  the  development  of  cancer,  a  process
                comprising sustained proliferation, evasion of growth suppressors, cell death resistance,
                replicative immortality, angiogenesis, metastasis and reprogrammed metabolism , tumor
                cells finally manage to evade immune destruction . The process that leads to the evasion of
                immune elimination is later described as immunoediting, because this includes all phases of
                interaction between cancer and immune system beyond immunosurveillance .


                The immunoediting hypothesis is composed of three phases: elimination, equilibrium and
                escape . This theory originates from microevolution in which the immune system selects
                for tumor cells that are best adapted and thereby the least immunogenic . During the first
                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-
                antigens (Table 1) resulting in elimination by the production and secretion of cytokines (e.g.
                interferon (IFN)-γ, α and β, tumor necrosis factor (TNF)-α, Interleukin (IL)-12, IL-15, etc),
                granzymes, perforins, and chemokines. Perforin or IFN-γ deficient mice, or rag2 deficient
                mice lacking functional T cells, are much more susceptible to tumor development compared
                to  immunocompetent  mice 18,19 .  The  phase  of  equilibrium  is  characterized  by  a  balance
                between tumor development and immune control, which might last as long as the lifetime
                of the host. This has been validated by studies showing that administration of a low dose
                carcinogenic substance to immunocompetent mice, induced tumor formation, but could
                be controlled. However, if certain components of the immune system were corrupted, for
                instance by antibodies depleting lymphocyte populations or cytokines, this disrupted the
                established equilibrium .
                Tumor  cells  that  develop  escape  mechanisms  to  interfere  with  components  of  the
                immune system themselves can also avoid elimination and tumor control. One of these
                mechanisms is avoiding the recognition by the immune cells. Recognition of tumor cells
                by CD8 T cells depends on the expression of classical MHC class I molecules to present
                tumor antigens (Figure 1A). Antigen loss and loss or downregulation of MHC expression is

                 GENERAL INTRODUCTION                                                    9
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