Epigenetic markers for melanoma patient response to ICB therapy

Melanoma is one of the most common cancers in the UK, with over 15,000 incident cases each year. The introduction of immune checkpoint blockade (ICB) therapy (also known as checkpoint inhibitor therapy) has revolutionised the treatment of patients with advanced or metastatic melanoma. The result of this is both an increase in the life expectancy and cure rates of patients diagnosed with this historically fatal disease.

ICB therapy works by blocking the activity of immune-suppressing proteins that stop the immune system from attacking cancer cells. By doing so, the immune system ‘activates’ and releases cells known as T-cells, allowing them to destroy the cancer. However, not all patients experience long-lasting clinical benefits to this treatment and the agents involved can lead to significant immune-related toxicity. This therapy is also of limited use when cancer treatment has already begun.

There is a need to identify new markers that will help to determine how a patient will respond to ICB therapy and for which of them the immune related side-effects will be severe. These new markers may help clinicians to define who would respond best to ICB treatment, and who should use alternative treatment options.

Dr Rosalin Cooper, and group leader, Dr Benjamin Fairfax were recently awarded a CRUK Oxford Centre Development Fund grant to investigate the use of novel cell-free DNA (cfDNA) techniques to determine its potential use as one of these markers.

In patients with cancer cfDNA can be released by the tumour, and has been shown to have increasing potential as a marker to identify the presence of cancer. It’s easy to access through simple blood samples, or ‘liquid biopsies’, and provides a wealth of data, such as information on epigenetic modifications.

In addition to the information stored in the genetic sequence of the cfDNA, epigenetic modifications to DNA (such as methylation and hydroxymethylation of cytosine residues) are also thought to be indicative of the location and type of tumour a patient has and are thus an attractive candidate to monitor the immune responses to cancer.

Rosalin intends to characterise the epigenetic landscape of cfDNA in melanoma patients in order to identify signatures of epigenetic modifications that are indicative of the extent a tumour is sensitive to ICB treatment and the likelihood of it triggering a potentially toxic side-effects.

Thus far the team have already characterised the 5-hydroxymethylation profiles of a small number of metastatic melanoma patient, before and after treatment with ICB. They found significantly different levels of DNA hydroxymethylation after treatment including changes in hydroxymethylation around genes involved in the immune response and that code for cancer-related pathways.

Using CRUK Oxford Centre Development funding to expand the number of patients tested in this way will help to determine whether these changes predict for which patients ICB is the best treatment option.

About the researchers

Dr Ros Cooper, Weatherall Institute of Molecular Medicine, is a CRUK Clinical Research Training Fellow who characterises immune responses to checkpoint inhibitor therapies.

Dr Ben Fairfax, Department of Oncology, focuses on the genetic and epigenetic determinants of inter-individual variation in immune responses.