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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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