Research

Apoptosis, a form of programmed cell death, is an essential process for the removal of senescent or damaged cells in the body. Indeed, the ability of immune cells to trigger apoptosis in target cells is an essential mechanism for the elimination of potentially dangerous cells. Failure to remove aberrant cells can allow such cells to develop into a tumour. Moreover, at the end of immune responses, activated immune cells need to be removed to terminate the inflammatory process and allow the body to revert back to homeostasis. Failure to remove such activated immune cells can lead to tissue damage and autoimmune diseases.

Cytotoxicity: A key mechanism by which cytotoxic lymphocytes, Natural Killer (NK) and cytotoxic CD8+ T cells, kill unwanted cells is through the death-ligand TRAIL (‘TNF-related apoptosis-inducing ligand’ or CD253). The binding of TRAIL to its death receptors (DRs) DR4 (CD261) or DR5 (CD262) induces an intracellular signalling cascade leading to apoptosis. A unique feature of TRAIL, among other death ligands, is its exceptionally high selectivity for malignant or senescent cells, with very low cytotoxicity towards healthy, normal cells, even if they express DRs. This makes the TRAIL/DR apoptotic system a particularly interesting therapeutic target as engaging DR4/DR5 on e.g. tumour cells can induce the cell death of these malignant cells without harming the surrounding healthy tissue.

The problem: However, tumour cells can escape this selective pressure of the immune surveillance. One important mechanism of this tumour evasion is the ability of some cancer cells to alter the signalling downstream of DRs from a canonical pro-apoptotic signal towards an alternative, non-canonical survival signal. Such non-canonical DR-signalling not only bypasses apoptosis but also promotes tumour growth and aggressiveness. Importantly, TRAIL-4-Life consortium members discovered that such non-canonical DR-signalling can also modulate the function of immune cells. However, many aspects of the non-canonical DR-signalling and its role in tumour and immune cells are still unknown.

The main aim of the TRAIL-4-Life consortium is to use our mechanistic understanding of the non-canonical DR-signalling pathway and its related cellular processes in tumour and immune cells for therapeutic purposes.

To this end, the consortium combines the multidisciplinary expertise of our partners and applies a wide set of state-of-the-art in silico, in vitro, and in vivo approaches.

These specific goals are currently addressed by TRAIL-4-Life:

To obtain a comprehensive understanding of the non-canonical DR-signalling pathway in tumour and immune cells. Insights will be obtained on both depths and breath dimensions: (i) On the one hand, we will analyse the non-canonical DR-signalling pathway in detail on the genetic, protein, and cellular levels. (ii) On the other hand, we will measure the relevance of the non-canonical DR-signalling pathway in various tumour types and auto-immune diseases.
To develop novel small molecule inhibitors (SMIs) to inhibit the non-canonical DR-signalling pathway to sensitise e.g. tumours again towards TRAIL-induced cell death.
To develop cell-targeting nanovehicles incorporating synergistic inducers of cytotoxicity and to demonstrate their therapeutic efficacy in in vitro assays (human, mouse) and in vivo mouse models of tumour and auto-immunity.

With this work TRAIL-4-Life will translate our knowledge of the TRAIL/DR death signalling pathway into novel diagnostic and therapeutic tools to treat cancer and auto-immune diseases.