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Introduction

            Effector mechanisms - Granule-exocytosis pathway

            To eliminate cancer cells, cancer immunotherapy restores or enhances the effector function
            of CD8+ T cells, NK cells, or other cytotoxic cells in the TME. Cytotoxic lymphocytes  use
            two main mechanisms to induce tumor cell or virally-infected cell death: 1) Granule exo-
            cytosis pathway, in which granzymes, along with the pore-forming protein perforin, trigger
            apoptosis. 2) Death receptor pathway, in which death receptors such as Fas on immune cells   1
            crosslinks with Fas Ligand on tumor cells, thereby initiating apoptosis in the latter. The gran-
            ule-exocytosis pathway is thought to be most important for clearance of tumors (Figure 1)
            [10-12].


































            Figure 1. Granule-exocytosis pathway depend on perforin and granzymes. TCR activation triggers
            cytotoxic granule release from cytotoxic cells towards the target cells. These granules contain perforin
            and a set of five granzymes. After recognition and conjugation with a target cell, the cytotoxic lym-
            phocyte cytoplasmic granules move to the site of cell-cell contact and their contents are released into
            the intracellular space. Perforin makes pores in the plasma membrane, allowing granzymes to enter the
            target cell. Here, granzyme trigger caspase-dependent and caspase-independent death pathways to kill
            the target cell [13, 14]. Except to induce apoptosis of target cells, granzymes can also exist extracellu-
            larly and employ noncytotoxic functions, including modulation of angiogenesis, promoting cytokine
            release, cleaving extracellular matrix components, or cleaving cell-surface receptors [15, 16]. ECM:
            extracellular matrix; TCR: T cell receptor; MHC: major histocompatibility complex.

            Perforin

            Perforin is a 70 kDa glycoprotein able to polymerize and form a channel in the target cell
            plasma membrane allowing granzymes entry. In the present thesis, we also use the bacterial


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