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Blocking energy production in immune cells helps tumours escape treatment

March 03, 2020

A small molecule that inhibits energy production in immune T-cells allows some tumours to escape treatment with an immunotherapy called PD-1 blockade therapy, says a study in mice published today in eLife.

Cancer therapies that help boost the immune system's defences to tumour cells are a promising new approach to treatment. One such therapy blocks PD-1, a receptor on the surface of T-cells. Cancer cells express a protein that binds to this receptor and interferes with the T-cell's ability to kill tumour cells. But while drugs that block this receptor can reactivate the T-cells, they are not always effective and the results of the new study help explain why.

"Despite the great success of PD-1 blockade therapy, we need to improve its efficacy because more than half of patients' tumours don't respond to it," says lead author Alok Kumar, a PhD student in the Department of Immunology and Genomic Medicine at Kyoto University, Japan.

To learn why so many tumours fail to respond to PD-1 blockade therapy, Kumar and his colleagues studied mice with two types of tumour cells: some that were sensitive to PD-1 blockade therapy and others that were not. This allowed the team to identify two different types of tumours that do not respond to PD-1. One type suppressed the immune system and caused even the PD-1-sensitive tumour cells to grow, while the other had no effect on PD-1-sensitive tumour cells.

"We found that some human cancer cells release immunosuppressive molecules that inhibit the activity of energy-producing mitochondria in T-cells," Kumar explains. Treating the mice with a mitochondria-boosting compound reversed this effect in the immune-suppressing tumour.

However, the treatment had no effect on the other type of tumour. Instead of impairing energy production in T-cells, the other tumour made itself invisible to the immune system by failing to produce a protein that helps immune cells recognise tumour cells.

The identity of the molecule that helped the first type of tumour suppress mitochondria is currently unknown. The researchers hope that if they can find it, they can create drugs that hinder its activity. "If we could identify these unknown factors and develop drugs that block them, we could save patients' lives by using the drugs alongside PD-1 blockade therapy to prevent tumours from defending themselves," says senior author Tasuku Honjo, Professor of Immunology and Genomic Medicine at Kyoto University.
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Reference

The paper 'Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy' can be freely accessed online at https://doi.org/10.7554/eLife.52330. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

This study will be included in eLife's upcoming Special Issue: 'Discovery and Translation of Cancer Immunology'. To be alerted as new papers are published, follow #eLifeCancerImmunology on Twitter.

Media contact

Emily Packer, Senior Press Officer
eLife
e.packer@elifesciences.org
01223 855373

About eLife

eLife is a non-profit organisation inspired by research funders and led by scientists. Our mission is to help scientists accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours in science. We publish important research in all areas of the life and biomedical sciences, including Immunology and Inflammation, which is selected and evaluated by working scientists and made freely available online without delay. eLife also invests in innovation through open-source tool development to accelerate research communication and discovery. Our work is guided by the communities we serve. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, the Wellcome Trust and the Knut and Alice Wallenberg Foundation. Learn more at https://elifesciences.org/about.

To read the latest Immunology and Inflammation research published in eLife, visit https://elifesciences.org/subjects/immunology-inflammation.

About Kyoto University

Kyoto University is one of Japan and Asia's premier research institutions, founded in 1897 and responsible for producing numerous Nobel laureates and winners of other prestigious international prizes. A broad curriculum across the arts and sciences at both undergraduate and graduate levels is complemented by numerous research centres, as well as facilities and offices around Japan and the world. For more information please see http://www.kyoto-u.ac.jp/en.

eLife

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