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Death receptor signalling in tumour immune editing

Periodic Reporting for period 2 - DISCOVER (Death receptor signalling in tumour immune editing)

Reporting period: 2020-01-01 to 2022-12-31

During tumour development there is a bi-directional communication between cancer cells and immune cells; the process termed tumour immune editing. The impact is reciprocal, shaping both the visibility and susceptibility of the tumour to immune eradication as well as the ability of the immune effector cells to recognise and launch an immune response against tumour cells. Immune cells kill tumour cells using proteins, called death ligands, that they carry on their surface. These death ligands bind to so-called death receptors, often present on the surface of the cancer cells. This binding initiates a suicide programme in the cancer cell. As tumours evolve, this process becomes less effective, allowing the tumour cells to overgrow.
The aim of the DISCOVER project is to bring a collaborative research network together to determine how exactly these proteins work and how their role evolves in tumour - immune cell interactions.
The research programme is focused on an interdisciplinary area between immunology and cancer cell biology, which – despite its huge importance – is currently underexplored.

The overarching aim of the DISCOVER programme is to address the role of the death ligand-death receptor signalling system across the three phases of tumour immune editing (elimination, equilibrium and escape).

The aim will be addressed across three specific objectives:
1. Identify approaches to block death receptor-induced tumour cell invasion driving metastasis
2. Determine strategies to block tumour immune tolerance
3. Identify mechanisms to activate novel pathways of DR-mediated tumour cell death

Overall, DISCOVER will have a strong potential to discover new targets for therapy and therapeutic lead molecules with commercial value, which will open new avenues of research and lead to follow-on work in this promising area.
During the first two years of the DISCOVER programme we have made the following discoveries. The research had two main activities, firstly to look at DRs and their function in tumour cells and secondly to look at DLs and DRs in the immune cells.
It is now well known that cancer cells, although carry DRs on their surface, these receptors have altered function. DISCOVER researchers showed that DRs are often dysfunctional in inducing the suicide programme. Instead when they bind with DLs, they initiate migration of the cancer cells, a key step in forming metastasis. We found what one key mechanism driving DR-induced migration and identified a chemical compound that can block this migration. This compound is hoped to be developed into a future therapeutic drug.
DISCOVER research examining the role of DRs and DLs in immune cells made on major discovery, where we showed that DLs can modulates the activity of Natural killer cells, one of the main immune cell type involved in tumour cell killing. Initial results show that the effect of DLs may restrict the anti-tumour activity of immune cells.
The objective of the third workpackage is to activate novel pathways of DR-mediated tumour cell death. The rationale for these studies is that DR-mediated cell death is often cancer cell-specific and consequently have very low unwanted toxicity. This project is at an early stage, where the experimental models have been set up. These models are now being used to delineate novel mechanisms through which DRs in cancer cells can be activated.
Progress beyond the current state of the art and expected results

Recent research showed that when the tumour cells become resistant to immune cell attack, the consequence is not only that the immune system becomes ineffective, but in fact worse. This is because when immune cells try to kill the tumour cells via the DL-DR pathway, instead of cell death, it initiates tumour cell migration, potentially driving metastasis. The work of the DISCOVER programme will increase our understand how this process take place, and how it can be blocked.
In addition to the various impacts of death ligands on tumour cell fate, it is equally important to consider the role of death ligands in regulating the function of immune cells. While immune cells are essential to protect the organs and tissues from infections and from the spread of malignant cells, overfunction of immune cells cause autoimmune diseases by damaging otherwise healthy tissues. Thus, the number and activity of immune cells have to be tightly controlled. In this regard, the DL-DR system is known to limit the activity of immune cells and function to prevent autoimmunity. During tumour immune editing, it is not only the immune cells applying selective pressure on the tumour cells, but reciprocally, the tumour cells also sculpt the functionality of the immune cells.
However, our knowledge is very limited about how the DL-DR controls the function of immune cells in a tumour. Our hypothesis is that the DL-DR system may be a main driver of the equilibrium phase and the consequent escape phases by limiting the activity of the immune cells against tumour cells.

Potential impact DISCOVER research will make

DISCOVER will impact on the career development of both early stage and experienced staff by developing their skills, expertise and their personal collaborative networks thus enhancing both career aspects and career prospects by equipping our researchers with state-of-the-art scientific knowledge and technical skills, work experience in an international research consortium, intersectoral work experience and working in an environment stimulating creativity and entrepreneurship.
Combined, the scientific and technical skillset DISCOVER members will receive will enable them to become leaders in the field, either in the academic or in the industrial sector. The long-term impact of DISCOVER on staff members will be promotion of their development into scientists with key boundary-spanning capabilities, who are innovation-oriented and can contribute their enhanced creativity and resourcefulness to tackling unmet clinical needs in cancer research.
Producing highly skilled researchers with key transferable skills who are able to exploit their scientific knowledge in an innovative and entrepreneurial manner has the potential to promote the ERA to the forefront of research and innovation in tumour immunology, an area that has economic and societal significance because of the current unmet need for innovative therapies for a large number of cancer patients.
DISCOVER will also create impact by developing new and lasting research collaborations, achieving transfer of knowledge between participating organisations and contribution to improving research and innovation potential at the European and global levels
Overall, DISCOVER will exploit the multidisciplinary and cross-sectional expertise of the participants, establishes excellent research, training and networking programme with top calibre researchers to make leaps in scientific and clinical understanding and applications, which will push Europe to the forefront of cancer immunology, drive innovation capacity and competitiveness.

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