Cancers that are resistant to radiotherapy could be rendered susceptible through treatment with immunotherapy and manipulating bowel cancers based on their "immune landscape" could unlock new ways to treat resistant tumours. A study by The Institute of Cancer Research (ICR), London, in collaboration with the University of Leeds and The Francis Crick Institute, found that profiling the immune landscape of cancers before therapy could identify patients who are likely to respond to radiotherapy immediately and others who might benefit from priming of their tumour with immunotherapy.
"Radiotherapy has revolutionised cancer treatment and is the most effective way of curing cancer other than surgery,” said Study leader Dr. Anguraj Sadanandam, leader of the Systems and Precision Cancer Medicine Team at the ICR. "Our study has shown that the immune landscape and levels of inflammation within cancers is crucial to determining how they respond to radiotherapy. It suggests that combining radiotherapy with immunotherapy could prove a highly potent mixture - improving our ability to eliminate hard-to-treat cancers further still. Now we want to improve our understanding of how to combine and sequence radiotherapy and immunotherapy together to maximise the treatment response for the individual biology of each patient."
The research teams studied inflammation in bowel tumour samples taken before and after radiotherapy from 53 patients. They aimed to understand how tumour immune activity before and after radiotherapy differs between patients who respond well and those who respond poorly to treatment. The team showed that the effectiveness of radiotherapy partly depends on the level of inflammation within tumours before and after treatment.
The study, ‘Differential and longitudinal immune gene patterns associated with reprogrammed microenvironment and viral mimicry in response to neoadjuvant radiotherapy in rectal cancer’, was published in the Journal for ImmunoTherapy of Cancer, was supported by the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the ICR, and the Medical Research Council.
In the study, patients who showed a poor response to radiotherapy - with no substantial falls in numbers of tumour cells - started with chronically inflamed tumours, with high levels of activity in 40 immune genes. The level of inflammation within their tumours showed minimal changes following radiotherapy. The team showed that the effectiveness of radiotherapy partly depends on the level of inflammation within tumours before and after treatment.
In contrast, good responders - who saw a marked drop in the number of tumour cells during radiotherapy - started with a relatively low inflammation tumour landscape which revved up following treatment. Here, there was a significant increase in the activity of 198 immune genes including genes representing immune cells that can directly kill tumour cells.
Together, the findings show that carefully timing a combination of immunotherapy and radiotherapy, based on an assessment of the cancer's immune landscape, could provide a way forward for treating resistant cancers.
"Radiotherapy is commonly used in patients with rectal cancer and there are currently no validated biomarkers that reliably predict how well the cancer will respond. Patients who do not respond well to radiotherapy may still experience significant side effects despite no clinical benefit,” said Dr Nick West, Clinical Academic Fellow at the University of Leeds and Honorary Consultant in Gastrointestinal Pathology. "This study suggests that we can potentially improve the response in these patients through modulation of the immune system, which is a very exciting development. The study also showed that a novel technique developed at the University of Leeds, tumour cell density, can be used to objectively measure the degree of tumour response to radiotherapy."
Although the study was carried out specifically in bowel cancer the researchers believe the findings could be relevant for other types of the disease too, particularly for cancers where surgery is not an option and radiotherapy is particularly important.
Increasing evidence shows that radiotherapy not only works by causing DNA damage and cell death in cancer cells but also in potentially a similar way to a vaccine - priming the immune system to recognise tumour cells and ramp up an immune response to attack them.
"Radiotherapy is an important curative treatment option for many patients with cancer. We are starting to understand how the immune response is important for radiotherapy to work most effectively,” said study co-author, Dr Anna Wilkins, Clinical Research Fellow in the Clinical Trials and Statistics Unit at the ICR, now at The Francis Crick Institute. “Our study suggests that by targeting specific non-cancer cells that block this immune response we can further improve radiotherapy responses in patients."
This work is part of growing activity at the ICR and in radiotherapy and immunology which includes the RadNet radiotherapy research network, in collaboration with The Royal Marsden.
"This fascinating study adds to the evidence that the effectiveness of radiotherapy is closely intertwined with the involvement of the immune system. It's now clear that the radiotherapy response in cancer cells and surrounding tissues can empower a patient's own immune system to recognise and destroy their tumour,” added Professor Paul Workman, Chief Executive of the ICR. "But radiotherapy requires a healthy immune response, and the new research suggests we might need to tune that response through immunotherapy. It could provide a foundation for future trials to test new combinations of drugs, including immunotherapies alongside radiotherapy."
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