Tumour cells use a protein called ART1 to kill immune cells that would otherwise attack them after radiotherapy. This matters because many patients with lung cancer and head and neck cancer do not respond to the standard combination of radiotherapy and immunotherapy, and doctors do not know why. The researchers have shown that radiotherapy makes tumour cells produce more ART1, which then destroys immune cells by modifying a receptor on their surface called P2X7R. In mice, blocking ART1 with an antibody shrank tumours and allowed more immune cells to enter. The team has also identified a second protein, CD38, that breaks down the molecule ART1 needs to function, potentially protecting immune cells. If this research succeeds, it could lead to drugs that target ART1, making radiotherapy-immunotherapy combinations effective for more patients. That would directly improve survival and quality of life for people with these cancers, rather than changing infrastructure or industrial systems.
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Patients with lung cancer (NSCLC) and head and neck cancer (HNSCC) are commonly treated with radiotherapy. Recent studies have shown that combining radiotherapy with immunotherapy improves outcomes for some patients. However, large patient groups do not respond to this combination treatment and the underlying causes for resistance are currently unknown. My project aims to test how a protein called ART1 could cause cancers to resist treatment. When cancer cells are stressed or die from cytotoxic treatments like radiotherapy, they release danger signals (ATP and NAD+) that alert the immune system and activate immune cells. These molecules act by binding to a receptor called P2X7R on immune cells which primes them to kill cancer cells. However, our recent work has shown that tumour cells can hijack this process by producing the ART1 protein. ART1 uses the NAD+ released in the tumour to modify the P2X7R on immune cells, resulting in their death instead of their activation. Our recent data shows that radiotherapy makes this process worse by promoting tumour cells to produce even more ART1. This shuts down the radiotherapy-induced immune response, causing the patient’s tumour to progress. Indeed, our analysis of tumours from NSCLC and HNSCC patients that did not respond to radiotherapy-immunotherapy treatment showed high ART1 and low P2X7R levels. We have developed an antibody that can block ART1 and reduce its immune suppressive effects. When we combined ART1 blockade with radiotherapy in mouse experiments, tumour growth reduced and more immune cells with P2X7R infiltrated the irradiated tumours. This suggests that targeting ART1 with drugs could improve the effects of combined radiotherapy immunotherapy treatment. We have also identified a potential novel role of another protein on immune cells, CD38. This enzyme breaksdown NAD+ in tumours, preventing ART1 from killing immune cells and allowing them to fight the tumours. This project has two main aims: First, to study how these three molecules, ART1, P2X7R, and CD38 interact, and are modified, in NSCLC and HNSCC patients undergoing radiotherapy or radiotherapy-immunotherapy.Our objectives for this aim are to understand their distribution in tumours and how they shape the immune response to cancer. Second, we will study (1) the mechanisms of how ART1 in cancer cells disrupts P2X7R –signalling, using mice treated with radiotherapy and immunotherapy, and (2) whether blocking ART1 and encouraging CD38 at the same time can protect anti-tumour immune cells, boosting their signalling through P2X7R, and counteracting radiotherapy-induced immune resistance. In summary, there is an urgent need to combat therapy resistance and tumour recurrence in NSCLC and HNSCC patients. This study will take a novel approach to understanding how tumours avoid radiotherapy-induced immune attack, and test new strategies that can enhance its effectiveness. Ultimately, ART1-targeting drugs could be a way to make more patients with NSCLC and HNSCC respond better to radiotherapy-immunotherapy combinations, improving their quality of life and life expectancy. Our team combines expert tumour immunology and radiation biology researchers with clinicians specializing in radiotherapy and immunotherapy of HNSCC and NSCLC. Pursuing this project at the ICR, with its world-leading translational infrastructure, cutting-edge mouse modelling facility, and renowned drug discovery programme sets us up for successful completion of our aims and will allow us to build upon our findings to develop ART1-targeting drugs and bring them to patients.
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