The immune systems of cancer patients are highly disrupted, with those who have a higher number of immune cells in their blood having a better survival rate, finds a new study that uses a pioneering technique developed by researchers at UCL and the Francis Crick Institute.
The tool, described in Nature Genetics, is called Immune Lymphocyte Estimation from Nucleotide Sequencing (ImmuneLENS). It enables researchers to calculate the proportion of T cells and B cells (types of immune cell) from whole genome sequencing (WGS) data for the first time.
Whole genome sequencing (WGS) uses a blood sample to create a complete record of an individual's DNA, the genetic instructions that determine who they are. By understanding these instructions, scientists can find out important information such as how many immune cells a person has, if there are any changes in their genes, and how their body is combating disease. This can be helpful for studying genetic illnesses such as cancer.
The team used ImmuneLENS to analyse over 90,000 WGS samples from the 100,000 Genomes Project, a study led by Genomics England and NHS England, which included the genomes of healthy individuals and cancer patients.
They found that cancer patients had a lower proportion of T cells circulating in the blood compared to healthy individuals. Further, T cell proportion was found to be a strong predictor of cancer outcomes, with higher proportions associated with 47% fewer deaths over a five-year period after surgery. This effect was still significant when accounting for age, cancer stage and across all cancer types.
The team say that these biological markers could be easily added to current genetic diagnostic tests, which would provide clinicians with more information on which to base treatment plans.
Professor Nicholas McGranahan, senior author of the study from UCL Cancer Institute, said: "Most immune system analysis until now has focused on the tumour itself, so the results we're seeing using this new technique - which examines the number of immune cells in a person's blood - are of considerable interest. What's going on with immune cells in the blood seems to have a huge impact on cancer survival and may be able to predict how long a cancer patient will survive better than the number of T cells in the tumour alone.
"There have been hints in previous research that this might be important, but being able to analyse immune system information at this scale is game changing. The ability to compare immune cell changes in the blood and to what's happening in the tumour environment opens up new avenues for cancer research, as well as healthcare research more widely.
"In terms of patient diagnosis and treatment, knowing whether a patient has relatively high or low numbers of immune cells in the blood, and how this corresponds to their prognosis, could help clinicians to decide on the best course of treatment for the individual."
Cancer is a disease primarily caused by genetic mutations in the body's cells, with certain mutations associated with particular types of cancer. While immune cells can recognise and eliminate dangerous mutations, cancer often evades this response and disrupts the immune system.
As such, assessing changes in both the area round the tumour (local immune environment) and in the wider immune system is crucial for understanding how cancer develops and predicting how a patient might respond to treatment.
Large-scale initiatives like the 100,000 Genomes Project, which holds whole genome data collected from over 90,000 NHS patients affected by rare disease or cancer, have allowed researchers to see the full spectrum of genetic changes within healthy and cancer cells. But the understanding of the precise immune cell makeup within both the tumour and wider immune environment hasn't been possible until now.
ImmuneLENS builds on a previous method from 2021 that enabled the proportion of T cells in whole exome sequencing data to be calculated.
While it is known that in healthy individuals the proportion of immune cells in the blood diminishes with age, the team found that this happens sooner in people with cancer.
This effect was more pronounced in male than female cancer patients, but it is not clear why these sexual differences exist or whether it has an influence on overall cancer survival.
They also observed that individuals who were seemingly healthy at the time their sample was taken for sequencing, who subsequently went on to develop cancer, had below average levels of B cells in their blood. This could be because of undiagnosed early-stage cancer, or pre-cancerous changes to the immune system that could potentially have been an early sign of disease or even a factor in cancer developing.
This information could be used in future for cancer early detection or to help clinicians understand how the patient may respond to treatment.
Dr Robert Bentham, first author of the study from UCL Cancer Institute, said: "Lots of approaches that measure immune cells from genetic data are like looking for a needle in a haystack. Our approach in this study instead looks at the haystack itself and asks how the presence of immune cells changes its overall shape. It's a different, more efficient way of finding the needle.
"One of the things this will allow us to do is to build significant immune datasets using data we already have from the many large-scale WGS cohorts but haven't been able to interrogate until now. It will allow researchers to explore what's happening in the immune system during health and disease, not just in cancer but potentially in many areas of medicine."
This method also allows different types of B cells to be easily distinguished from one another. As B cells mature, they specialise to produce a certain type of antibody (a protein whose role is to neutralise harmful substances such as viruses, bacteria and mutated cells). The team used this specialisation process to identify B cells and classify them.
When this method was applied to WGS data it revealed that B cells producing IgM/D antibodies in the blood (produced when the body first encounters a foreign antigen) were the only type of B cell associated with improved survival outcomes of cancer patients, suggesting that these cells may play a key role in anti-tumour immunity. They also have potential as a new biological marker for cancer diagnosis, making them a promising target for future research.
One of the next steps for the researchers will be to take advantage of these biological markers in the clinic, which they say could be added to the current battery of tests for cancer patients at no extra cost. Professor McGranahan and his team have recently received started a CRUK funded Biomarker Project Award to enable further work to translate this into the clinic.
This could be particularly useful for predicting a patient's response to immunotherapy, because while the proportion of T cells in a tumour is a known biomarker it cannot be measured using current standard genomic tests.
Research Information Manager at Cancer Research UK, Dr Nisharnthi Duggan, said: "Cancer Research UK is pleased to support this ongoing work investigating whether measuring immune cell levels in our blood can help predict cancer survival. We're living in a golden age of research where we can use patient data in sophisticated ways to help us better understand cancer and how to beat it.
"Further research is needed, but this could one day become a tool to help doctors personalise treatment for people with cancer."
The research is part of the Cancer Research UK-funded TRACERx project.
This research was made possible through access to the data and findings generated by the 100,000 Genomes Project, which is managed by Genomics England.
Links
- Professor Nicholas McGranahan's academic profile
- Dr Robert Bentham's academic profile
- UCL Cancer Institute
- UCL Faculty of Medical Sciences
Image
- Credit: Human T cells showing nuclei. A. Walker, L. Sharp & J. Pryde. Source: Wellcome Collection.
