A large-scale analysis of more than 5,000 tumour samples, covering 19 cancer types, has shed light on how different types of mutations may be seen by the immune system and could potentially help clinicians identify patients more likely to benefit from a new class of immunotherapies called checkpoint inhibitors.
It is already known that patients whose tumours have a large number of 'point mutations' can benefit from checkpoint inhibitors, but the researchers from the Translational Cancer Therapuetics Laboratory at the Francis Crick Institute, The Royal Marsden NHS Foundation Trust, the University College London Cancer Institute and the University College London NHS Foundation Trust have found that one type of mutation, called a 'frameshift indel', is especially important in relation to how well patients respond to these new drugs.
It is hoped 'frameshift indels' along with other measurements can be used as part of a predictive diagnostic test, to better select which patients will benefit from immunotherapy.
Immunotherapies have led to remarkable tumour responses and improved survival in a subset of cancer patients, notably in those with tumours of the kidney, lung or skin, but there are very few tools to aid patient selection.
The study is published in The Lancet Oncology and was funded by Cancer Research UK and the NIHR Biomedical Research Centres at The Royal Marsden and The Institute of Cancer Research (ICR) and University College London NHS Foundation Trust.
Researchers studied the genetic mutations in detail across 200 melanoma patients, and found that patients whose tumours had a high number of 'frameshift indels' responded better to checkpoint inhibitors compared to patients whose tumours had a low number of those mutations.
Lead study author, Dr Samra Turajilic, Cancer Research UK Clinician Scientist at the Francis Crick Institute and Consultant Medical Oncologist at The Royal Marsden said: "We are excited about the insights we have made as they add to the growing understanding of how cancer mutations impact patients' immune systems. We already know that patients with a high number of point mutations are more likely to benefit from checkpoint inhibitors, and now we show that this other class of mutations, 'frameshift indels' also contribute to the benefit from therapy. We are hopeful that in the future 'frameshift indels' will be included in diagnostic tests to help patient selection, but there remain many factors that affect treatment response that we need to understand."
The importance of 'frameshift indels' stems from the fact they can cause long strings of altered DNA. Point mutations typically change a single letter of the DNA code - such small scale change can be missed by the patient's immune system. However in the face of tens of mutated letters the authors believe the patients' immune system could be more likely to spot these errors and mount a potent immune response, which is subsequently 'released' by checkpoint inhibitors.
An additional finding in this study was that kidney cancers had the largest number of 'frameshift indels', more than either lung or skin cancers, which are typically among the most highly mutated tumours due to tobacco and sunlight exposure. Researchers say this may be one of the factors that explains why some kidney cancer patients respond well to immunotherapy even though they do not have many point mutations.
In addition the authors plan to explore whether frameshift indels can used therapeutically, as potent immune targets in tumour cell vaccinations or adoptive immune cell-based therapies.
