BACKGROUND

Tumour immune editing:

Tumour immune surveillance is the process by which immune cells detect and eliminate malignantly transformed cells. While this surveillance is very effective and eliminates most arising tumour cells, some tumour cells can escape and survive. The immune system can repress the growth of these escaped cells by creating a restrictive microenvironment where the tumour cells persist, usually as dormant cells. Tumour immune suppression may however fail or become exhausted, allowing unrestricted growth of the tumour cells. This evolving tumour-immune interaction is referred to as tumour immune editing. 

Tumour immune editing consists of three phases. The elimination phase is where the immune system can recognise cancer cells and can launch an effective cytotoxic reaction against them. The equilibrium phase is where the immune system and the tumour reaches a steady state equilibrium, where the tumour persists but does not grow in size. However in this phase, some tumour cells may proliferate and/or gain new characteristics that help them to become undetectable to the immune system, block activation of the immune cells or develop resistance mechanisms against immune-mediated cytotoxicity. When tumour cells develop a non-immunogenic phenotype by gaining some of the above characteristics, or if the immune system becomes exhausted, tumour growth is no longer repressed and the tumour will manifest (escape phase).

 

Death ligands and death receptors:

Death ligands (DL) are transmembrane or soluble cytokines produced by immune cells to kill death receptor (DR)-expressing cells, such as cancer cells. 

The mechanism how death receptors induce the death is well understood and the importance of this process in the elimination phase of tumour immune editing is broadly recognised. For example, cells undergoing malignant transformation become sensitive to the death ligand, TRAIL (TNF-related apoptosis-inducing ligand) and thus become targets for immune cells.

Another death ligand, FasL also has fundamental impact on tumour progression. It is shown that the death receptor for FasL (FAS) is frequently mutated in cancer and mutation of FAS allows cancer cells to escape from immune-attacks. 

On the other hand, the role of death ligands and death receptors in well-established tumours may be completely different. For example, FasL-FAS signalling supports tumour growth after malignant transformation took place, indicating that the DL-DR system can eliminate pre-malignant cells; but later, it may in fact support the growth or survival of transformed, overtly malignant cells.

In support of this, recent findings from DISCOVER consortium members have showed that DRs in some tumour cells mediate an altered, non-canonical signalling pathway, which has a direct, pro-tumorigenic potential as it drives enhanced tumour cell migration and invasiveness.

It appears that the mechanism through which DRs drive cancer cell motility is very different from the mechanism used to induce cell death. It requires a different segment (domain) of the DR (i.e. not the death domain), and dependent on calcium entry into the cell. However, the exact chain of events that leads to DR-driven tumour cell migration is not understood yet.

 

In addition to the various impacts of death ligands and death receptors on tumour cell fate, death ligands also regulate immune homeostasis. For example, TRAIL is a critical regulator of immune homeostasis by driving immune tolerance in tissues. Peripheral tolerance is the process that limits the autoimmune reaction by mature immune cells. 

Death ligands regulate peripheral immune tolerance by three processes. Firstly, they can kill reactive immune cells (activation induced cell death). Secondly, death ligands, especially TRAIL, drive the proliferation of regulatory immune cells (e.g. Tregs) to shut down the immune response. Thirdly, death ligands can inhibit immune cell activation and proliferation, for example by inducing cell cycle arrest. The fact that TRAIL is frequently expressed by cancer cells and its expression is associated with a shorter disease-specific survival suggest that DL-DR signalling may be a key contributor of tumour immune tolerance. 

In addition to the role of DR on the cell surface, there is accumulating evidence that DRs also function as intracellular receptors. Research from DISCOVER consortium members found that TRAIL receptors are essential for endoplasmic reticulum stress-induced cell death. Interestingly, intracellular TRAIL death receptors appear to act as cellular stress sensors and induce death upon prolonged, unresolved stress. Importantly, DRs function very differently intracellularly compared to their plasma membrane forms. While DRs on the cell surface can induce cell death, inflammation, differentiation or migration, intracellular death receptors have only been found to induce cell death. Death receptor-induced cell death is one of the few inducible cell death mechanisms that is not associated with DNA damage and induction of mutations, a feature that we can exploit to develop safer cancer therapeutics.