Gasdermin E: A new approach to cancer immunotherapy that could have broad reach

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Tumours have figured out various ways to prevent the immune system from attacking them.

Medicine, for its part, has fought back with cancer immunotherapies.

The major approach uses checkpoint inhibitors, drugs that help the immune system recognise cancer cells as foreign.

Another method, CAR T-cell therapy, directly engineers peoples’ T cells to efficiently recognise cancer cells and kill them.

But not all patients benefit from these approaches, which work for just a minority of cancer types, and CAR T-cell therapy carries significant risks.

New research from Boston Children’s Hospital, published in Nature, adds another strategy to the arsenal, one that could potentially work in more types of cancer.

It reactivates a gene called gasdermin E, harnessing an immune response we already have but that is suppressed in many types of cancer.

“Gasdermin E is a very potent tumour suppressor gene, but in most tumour tissues, it’s either not expressed or it’s mutated,” says Judy Lieberman, MD, PhD, of the Program in Cellular and Molecular Medicine (PCMM), the study’s principal investigator.

“When you reactivate gasdermin E in a tumour, it can convert an immunologically ‘cold’ tumour – not recognised by the immune system – into a ‘hot’ tumour that the immune system can control.”

In the study, Lieberman and colleagues showed that 20 of 22 cancer-associated mutations they tested led to reduced gasdermin E function. When they re-introduced gasdermin E in a mouse model, they were able to trigger pyroptosis and suppress growth of variety of tumours (triple-negative breast tumours, colorectal tumours, and melanoma).

The team also showed, in mouse tumour cell lines, how gasdermin E works.

Normally, when cells die, including most cancerous cells, it’s through a process called apoptosis, a quiet, orderly death.

But if gasdermin E is present and working, cancer cells go down in flames, through a highly inflammatory form of cell death called pyroptosis.

As Lieberman’s team showed in live mice, pyroptosis sounds a potent immune alarm that recruits killer T cells to suppress the tumour.

The team is now investigating therapeutic strategies for inducing gasdermin E to rally that anti-tumour immune response.

“What we’re suggesting is that if we can turn on the danger signal, which is inflammation, we can activate lymphocytes more fully than with other immunotherapy approaches, and have immunity that is potentially much broader,” says Lieberman.

“Combining activation of inflammation in the tumour with approved checkpoint inhibitor drugs could work better than either strategy on its own.”

Source: Boston Children’s Hospital


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The ONA Editor curates oncology news, views and reviews from Australia and around the world for our readers. In aggregated content, original sources will be acknowledged in the article footer.

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