Immune exhaustion linked to breast cancer in BRCA carriers

Thirteen per cent of women will develop breast cancer. It’s the most common female malignancy, accounting for a fifth of diagnosed tumour types. We know that family history and therefore genetics can play a powerful role in determining the risk of developing the disease, and some genes - particularly the BRCA1 and BRCA2 genes - can strongly load the dice. One in four hundred of us carry altered “high-risk” forms of these genes, which can give an individual a 70% likelihood of developing a breast cancer by age 80. Angelina Jolie famously underwent a preventative mastectomy ten years ago when she discovered that she was a carrier. What’s less clear is how these genes are tipping the balance towards developing cancers. To find out, a team at Cambridge University have picked apart, cell by cell, the make-up of breast tissue - including the immune cells found there - and interrogated what genetic programmes are operating in these cells among both healthy people and BRCA gene carriers. The purpose is to probe how the disease gets started. Austin Reed and Sara Pensa are the study’s authors…

Sara - One of the ways that we thought we could tackle this is by looking at how the healthy tissue looks and how risk factors; ageing, breastfeeding, and mutations in important genes that are called BRCA1 and BRCA2, would do to these otherwise healthy tissues.

Chris - Has no one, with all the years we've been studying this disease, actually picked their way through a breast and asked, well, what are all the cells that are in here?

Sara - There have been a few attempts, but we believe this is actually the biggest in the world. What makes it particularly special is that we've been able to collect donated tissues from women of all sorts of different ages and types, and the variety of the samples that we've been able to analyse have given us the ability to understand changes in response to different factors.

Chris - So what did you do with the tissue samples you had? You've got women who are healthy, you've got women who are carriers of some of these genetic conditions like BRCA - which we know increase your risk of breast cancer and other cancers - you've got some people who've actually got breast cancer, you've looked at the opposite breast. Austin, how did you then, when you were handed these samples, how did you process them?

Austin - Once we receive the donated tissue, we break it down into single cells and we read the genetic signalling for each of these cells for all of the donors. We then start to look at the patterns and trends and the gene signalling to try to give us insights into the changes that are happening in the breast and how they might link to the actual changes in risk that these donors might have.

Chris - Did anything leap out at you that might be linked to why certain people with certain genes get this disease?

Sara - Yes. One of the most important findings is we noticed that, in the tissues that were coming from individuals with these genetic mutations, we seem to have a very elevated number of immune cells in the tissue. Now, immune cells normally are there to protect us from disease from damaged cells, but what seemed pretty obvious is that these immune cells seem to be unable to function properly, they had signs of being, as we technically call them, exhausted.

Chris - Does this mean then that the immune response is there? It would normally be trying to stop a cancer forming, but it's basically becoming tired or fatigued so it's not going to be as good at doing that?

Sara - That's exactly what it is. What it is interesting is that this is normally found at late stage disease. This is something that is very commonly found in cancer. But what we were seeing here is this is happening already, much, much earlier.

Chris - So people who have BRCA, this gene that gives them a higher risk of cancer, this is trying to form a cancer all the time. The immune system is trying to stop that happening, but eventually it gets worn down and then a cancer escapes.

Sara - That's exactly what we think is happening. This is a combination of what you just described and changes that occur in the cells that then will become tumour cells themselves. There is a little bit of a dialogue going on there, and the signals that some cells are giving to other cells is exactly what's going wrong at some point. Then it makes these dangerous cells hide themselves from the immune system and therefore the immune cells cannot kill them anymore.

Chris - What are the implications of this, then? You've spotted that you seem to have this chronic inflammatory process with the immune system, there. The immune system appears to eventually be overwhelmed by the efforts of the tissue to try to become cancerous. What does this tell us then about what we might be able to do to stop it?

Sara - What is particularly interesting to us is that if we see all of this happening before the tumour forms in the first place, then maybe we can think of targeting these cellular changes before and use some sort of preventative therapeutic approach. One of the strengths of what we are doing is that a lot of drugs that target these cellular processes already exist in the clinic, are already used for either breast cancer itself or other types of disease. What we were thinking then is potentially we could use these drugs to prevent the disease instead.

Chris - Austin, we know that the genes which are linked to what we've just been discussing BRCA, they're expressed all over the body and a range of other tissues also have a higher risk of cancer when you carry them. So could you do the same study again for other organs and see if what we've just been hearing might be playing out elsewhere as well, such as in the prostate gland in men, ovaries in women, and so on?

Austin - Absolutely. BRCA1 and BRCA2 mutations, for example, are known to have increased risk for prostate cancers and ovarian cancers. Similar studies could absolutely be applied to look to see if similar mechanisms are at play in these other organs. There's not a huge amount that we've seen that suggests this has to be specific to the breast, and I think that would absolutely be a very interesting avenue to explore.

Chris - Is one implication of this then that you will put patients on these sorts of drugs to try to stop the immune system becoming exhausted in this way and then see if that reduces their risk of getting the cancers that they might otherwise have been destined to develop. Is that the next logical step in this study?

Sara - So this would be the next logical step, yes. But because of side effects that come with using these types of treatments, it's important to understand a little bit more about how this would work in preclinical settings first. So what we want to do is use a model of this disease and then try and use all sorts of compounds that already exist in the clinic. We would give these drugs to these models before they actually form breast tumours and see if we can prevent the onset of these tumours, in these models.