Genomic 'barcode tracker' scans immune cells in tumours

Tuesday, 23 July, 2019

Genomic 'barcode tracker' scans immune cells in tumours

Researchers from Sydney’s Garvan Institute of Medical Research have developed a new method to spot rare immune cells that are reactive against cancer cells, from within a patient’s own immune system.

Described in the journal Nature Communications, the patented method is said to enable scientists to track how immune cells evolve inside tumour tissue for the first time, revealing insights into how to better arm the immune system to target cancer. The technique can be likened to a barcode tracker, able to scan detailed information from thousands of immune cells at a time.

Immune cells come in many different forms — they mix and match different types of ‘receptors’ on their cell surface, which monitor the cell’s environment. When an immune cell’s receptors recognise a potential hazard, the cell replicates to make more copies of itself, able to target the threat more effectively.

Unfortunately, the immune system often responds poorly to cancers as they arise from the body’s own cells — usually too few immune cells ‘recognise’ them to mount an effective immune response.

“The immune cells that recognise cancer cells are often rare,” said Associate Professor Alex Swarbrick, who heads the Tumour Progression Laboratory at Garvan. “We have to sort through thousands of cells to find these replicating cells that may make up only a small fraction of all the immune cells present in a tumour.”

Previous methods have made it possible to read the long stretches of genetic output (RNA) that encodes an immune cell’s receptor, but they have not had the capacity to sort through the thousands of cells present in a tumour at a single time. So the study authors developed their own method by harmonising four different sources of genomic technologies: Oxford Nanopore Technologies, 10x Genomics, Illumina and CaptureSeq.

The team first developed a way to enrich the RNA from single cells, targeting the RNAs encoding the immune cell receptors. They then developed a computational tool to accurately read full-length sequences of the immune cell receptors.

The resulting ‘Repertoire and Gene Expression by Sequencing’ (RAGE-seq) method works much like a barcode tracker. By ‘scanning’ the relevant immune cell receptors in many thousands of cells at once it can provide an accurate snapshot of how the immune cells in a tissue sample are related, and which cells may be effective at mounting a response against cancer.

In a proof-of-principle study, the researchers used the method to sample 7138 cells from the tumour and associated lymph node of a breast cancer patient. The team pinpointed a number of related cells that were present in both tissues, and which revealed specific genetic signatures of the immune response within the patient’s tumour.

“This method gives us the most detailed view yet of how immune cells behave in the human body,” said Professor Chris Goodnow, Executive Director of the Garvan Institute and co-senior author of the study.

The researchers say the ability to find and barcode these rare cells of the immune system has the power to guide treatment strategies based on the individual. It should result in an improved form of immunotherapy, as current methods used to assess a patient’s response to the treatment give a poor snapshot of the behaviour of their immune cells.

“We hope RAGE-seq will be implemented in clinical trials, providing crucial information that will help potential cancer therapeutics get to the right patients more quickly,” Prof Goodnow said.

The team is now applying the technique to samples from melanoma patients, to understand why half of patients receiving immunotherapy have a poor response. The researchers believe the method could also be applied to provide a better understanding of autoimmune and inflammatory diseases.

Image credit: ©ürgen Fälchle

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