‘Exhausted’ immune cells in healthy women could be target for breast cancer prevention

New study uncovers the potential of immunotherapy in preventing breast cancer and creates the openly available Human Breast Cell Atlas

Everyone has BRCA1 and BRCA2 genes, but mutations in these genes – which can be inherited – increase the risk of breast and ovarian cancer. 

Researchers at the University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI), and the Wellcome Sanger Institute have created the world’s largest catalogue of human breast cells, which has revealed early cell changes in healthy carriers of BRCA1 and BRCA2 gene mutations. 

This study, published in the journal Nature Genetics, found that the immune cells in breast tissue of healthy women carrying BRCA1 or BRCA2 gene mutations show signs of malfunction known as ‘exhaustion’. This suggests that the immune cells can’t clear out damaged breast cells, which can eventually develop into breast cancer. This is the first time that ‘exhausted’ immune cells have been reported in non-cancerous breast tissues at such a scale. Usually, cells in this state are only found in late-stage tumours. 

The results raise the possibility of using existing immunotherapy drugs as an early intervention to prevent breast cancer from developing in carriers of BRCA1 and BRCA2 gene mutations.  

“Our results suggest that in carriers of BRCA mutations, the immune system is failing to kill off damaged breast cells – which in turn seem to be working to keep these immune cells at bay,” said Walid Khaled in the University of Cambridge’s Department of Pharmacology and Wellcome-MRC Cambridge Stem Cell Institute. “We’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations. Drugs already exist that can overcome this block in immune cell function, but so far, they’ve only been approved for late-stage disease. No one has really considered using them in a preventative way before.” 

The human breast cell atlas

Using samples of healthy breast tissue collected from 55 women across a range of ages, the researchers catalogued over 800,000 cells. The resulting Human Breast Cell Atlas is now available as a resource for other researchers to use and add to. It contains huge amounts of information on other risk factors for breast cancer, including Body Mass Index (BMI), menopausal status, contraceptive use, and alcohol consumption. 

“We used state-of-the-art single-cell RNA sequencing to map out the diverse makeup of breast tissue to build the Human Breast Cell Atlas,” said John Marioni, Visiting Group Leader at EMBL-EBI and Senior Vice President and Head of Computation at Genentech Research. “This effort has helped to highlight the complex relationship between cell dynamics and the risk of breast cancer. By sharing this dataset, we hope to encourage worldwide collaboration, inspiring further investigation and new breast cancer research.”

Understanding breast cancer risk factors

This new study aimed to understand how certain risk factors interact, by characterising the different cell types in the human breast under many different physiological states. 

To do this, the researchers used a technique called single-cell RNA sequencing to characterise the many different breast cell types and states. Almost all cells in the body have the same set of genes, but only a subset of these are switched on in each cell – and these determine the cell’s identity and function. Single-cell RNA sequencing reveals which genes are switched on in individual cells. 

“Breast cancer occurs around the world, but social inequalities mean not everyone has access to treatment,” said Sara Pensa, Senior Research Associate in the University of Cambridge’s Department of Pharmacology and joint first author of the study. “Prevention is the most cost-effective approach. It not only tackles inequality, which mostly affects low-income countries, but also improves disease outcome in high-income countries.”  

This press release was originally published on the University of Cambridge website.

Funding

The research was primarily funded by the Medical Research Council and Cancer Research UK. 

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bioinformatics, breast cancer, embl-ebi, genomics, press release, single-cell sequencing