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Dozens of new gene targets for cancer immunotherapy found

14 August 2017

By Ebtehal Moussa

Appeared in BioNews 913

Over a 100 new genes that may be essential for cancer immunotherapy to work have been identified using a new CRISPR-based screen. 

Immunotherapy is a mode of treatment which uses a patient's own immune system to destroy cancer cells. IT can be highly effective for some patients, but not all.

'This is the first step for systematically identifying the reasons immunotherapy is not working for many cancer patients,' said senior author Dr Nicholas Restifo at the National Cancer Institute in Bethesda, Maryland. 'The hope is to help scientists and clinicians find a way around the obstacles so that more patients can benefit from this promising treatment modality.' 

The research, published in the journal Nature, indicates that mutations in tumour cells cause them to go unnoticed by key immune system cells called T-cells, which prevents response to immunotherapy.

Researchers created a novel 'two-cell type' CRISPR assay consisting of human melanoma cells and T-cells, to investigate how these cells interact. They used CRISPR/Cas9 to knock out single genes in the human melanoma cells in order to identify which ones create resistance to T-cells.

'We cast a wide, deep net and conducted an unbiased survey of all of the 19,000 genes in the cancer's genome - not just the genes that are known to be involved in creating immunotherapy-resistant tumours,' said Dr Restifo. 'The big surprise was that we found many new genes that we never suspected could potentially be involved in preventing the immune system from killing cancer cells.'

The 100 most necessary genes were found to affect the presence of proteins specifically found on the surface of cancer cells, known as neoantigens. These are usually recognised by T-cells and trigger the release of cytokines, proteins which modulate the body's immune response.

Next, the researchers assessed 36 different cancer types for expression of these genes, searching genetic data from nearly 11,500 tumours from the Cancer Genome Atlas database. They identified a core set of 19 genes associated with cytokine activity across different cancer types. The researchers also found mutations in these genes were more common in patients who did not respond to the drug ipilimumab, a type of immunotherapy.  

In particular, the researchers identified multiple mutations in the APLNR gene, which had previously not been linked to the effectiveness of cancer immunotherapy. When they mutated APLNR in mice, it reduced the efficacy of immunotherapy.

Dr Restifo told Genetic Engineering and Biotechnology News that he hoped the findings could act as a 'blueprint' for further research into cancer therapies that hinge on T-cell attack. 'Looking at mutations in these genes in individual patients who failed immunotherapy may enable physicians to devise the most appropriate treatments for each individual patient, according to their essential gene profiles,' he said.

RELATED ARTICLES FROM THE BIONEWS ARCHIVE

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12 June 2017 - by Ebtehal Moussa 
Two trials of a new gene therapy have successfully treated blood cancers in patients who were unresponsive to standard treatment...
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12 December 2016 - by Ayala Ochert and Ebtehal Moussa 
Researchers have successfully treated a woman with colon cancer using her own immune cells to target a cancer-causing gene that had previously been considered 'undruggable'...
07 March 2016 - by Dr Molly Godfrey 
Scientists have identified a method by which all the cells in a tumour could potentially be recognised and eradicated by the patient's own immune system...
07 January 2013 - by Dr Greg Ball 
Immune cells that can recognise and kill cancer cells have been grown from induced pluripotent stem cells (iPSCs)...

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