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European Biopharmaceutical Review

Firing Up

Recent advances in immunotherapy, with the discovery of checkpoint inhibitors, have revolutionised the treatment of cancer. The key importance of the interplay between tumours and immune cells is now coming to the forefront. How cancer cells interact with the immune microenvironment is an area of rapidly expanding knowledge. The role of endogenous and exogenous DNA damage in activating the innate and adaptive immune response (IR) is becoming more significant – for example, using exogenous DNA damaging agents to prime the immune system or using endogenous DNA damage response deficiency (DDRD) as a potential biomarker to identify patients for immunotherapies.

Chemotherapy and IR

Although DNA-damaging agents were designed to directly target cancer cells, their interaction with the immune system now recognisably contributes to chemotherapy responses (1). This was first noticed in the 1970s when studies of the mechanism of action of anthracyclines suggested an immune component was involved in response to these agents, with an improved reaction in immuno-competent compared to immuno-compromised mice (2).

DNA-damaging agents such as anthracyclines and oxaliplatin are now known to induce immunogenic cell death through a threestage process. First, calreticulin is expressed on the surface of dying cells – an ‘eat me’ signal – leading to phagocytosis of dying tumour cells by dendritic cells. Next, adenosine triphosphate, released by dying cancer cells, recruits more dendritic cells to the tumour site, resulting in mature dendritic cells with specific major histocompatibility complex (MHC) Class 1 and 2 for the tumour cells. Finally, the release of high mobility group box protein 1 (HMGB1) from the nucleus binds to toll-like receptor 4 (TLR4) on dendritic cells and produces improved crosspresentation of tumour antigens.

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Dr Eileen Parkes is an academic clinical lecturer at Queen's University Belfast, Northern Ireland. She completed her PhD on the IR to DNA damage, identifying constitutive activation of the STING immune pathway in endogenous DNA damage by investigating the biology underpinning the DDRD subgroup. She is also a specialist in medical oncology at the Northern Ireland Cancer Centre.

Dr Nuala McCabe graduated from Queen’s University Belfast, Northern Ireland, in 1997 with an honours degree in biomedical science. She then gained her PhD training in the Department of Oncology at Queen’s University Belfast in 2001, investigating the role of the BRCA1 tumour suppressor in DNA damage response. Following this, Nuala then worked as a postdoctoral researcher with Professor Alan Ashworth in the Breakthrough Breast Cancer Research Centre (Institute of Cancer Research, London). During this time, she was involved in the identification of PARP1 inhibitors for the treatment of BRCA-associated breast and ovarian cancers, which are now approved by the EMA.

Professor Richard Kennedy is the Medical Director of Almac Diagnostics and CLIACompliant Laboratory Director. He is responsible for the application of the company’s technology into medical practice. Richard graduated in medicine from Queen’s University Belfast, Northern Ireland, in 1995. As a postgraduate, he trained as a medical oncologist and received a PhD in molecular biology in 2004.

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Dr Eileen Parkes
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Dr Nuala McCabe
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Professor Richard Kennedy
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