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Gene that cloaks cancer cells from the immune system found

22 July 2019
Appeared in BioNews 1007

Researchers have identified a gene, active in the early stages of development, that may help conceal cancers from common immunotherapy treatment.

Drs Robert Bradley and Stephen Tapscott at the Fred Hutchinson Cancer Research Centre in Washington, mined the genetic profiles of 9759 cancer samples from 33 different cancer types (from the NIH Cancer Genome Atlas programme) to find genes that regulate interactions between tumours and the immune system.

The study, published in Developmental Cell, showed that patients with an active DUX4 gene – usually inactive in healthy adults – were less likely to respond to a class of immunotherapy drugs, known as checkpoint inhibitors. These inhibitors are effective at enabling the body's immune system to attack cancer cells; however, for previously unknown reason, a majority of cancer patients do not respond to them.

Dr Bradley said: 'This study is an example of the unexpected things you can learn from large-scale genomic data.'

It also adds to the understanding of early embryo development, as the researchers hypothesised that this gene may also protect the embryo from the mother's immune system. 

'DUX4 is normally turned on in the very early embryo,' said Dr Bradley. 'This is a very special time because the embryo has foreign genetic material relative to the maternal tissue.'

Dr Tapscott previously studied the role of DUX4 in muscular dystrophy before discovering its expression in bladder, breast, lung and stomach cancers. Considering the fact that DUX4 is expressed in many cancers, it's hoped that development of new drugs that selectively turn the gene off could make checkpoint inhibitors more effective in a wider number of patients. 

'Immunotherapy can be incredibly powerful against previously untreatable cancers, but it isn't effective yet for most patients,' said Dr Bradley. 'Understanding the mechanisms that prevent the immune system from identifying and attacking tumours is a first step toward finding cures for all cancer patients.'

Dr Tapscott also noted that there is no increase in cancer risk among individuals with muscular dystrophy, suggesting that DUX4 might be used by cancer cells to escape immune surveillance by reactivating an early embryonic development programme, rather than as a driver that causes cancer.

The study authors plan to use larger cohorts to confirm their findings and test the clinical utility of using DUX4 activity to predict response to immunotherapies. They also aim to determine why DUX4 expression causes immune attack in muscular dystrophy but immune evasion in cancers, which may give some new insights into treating muscular dystrophy.

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