The immune system is quite a terrific thing… It’s extremely effective at getting rid of TONS of bacterial and viral infections that have the ability to harm us. But cancer, that’s a different story… It starts from directly within our own cells, which can quickly grow quite out of control, and then poses a colossal challenge for the immune system.
Scientists have long known that, for some cancers at least, employing devious methods to trick or hide from the immune system is paramount to their survival.
And in recent years, ‘immunotherapy’ treatments, which unleash the power of the immune system by unmasking tumours and encouraging immune cells to attack them, have been showing great promise.
Today, Professor Caetano Reis e Sousa and his Cancer Research UK-funded team at The Francis Crick Institute have revealed another trick up cancer’s sleeve – and their discovery could lead to a simple way to boost the power of immunotherapy treatments.
And it centres on aspirin – one of the most widely available drugs, and one whose complex role in cancer has come under close scrutiny.
Prostaglandins and COX
Professor Reis e Sousa and his team were interested in a particular chemical signal – called prostaglandin E2 – which is normally released by our blood vessels, and can affect how the immune system responds to problems.
Prostaglandin E2 is a molecule with a split personality. On the one hand it causes inflammation, calling immune cells into infected or damaged areas (for example a skin cut) so they can get to work on clearing up the problem.
And it’s this role in suppressing T cells that makes prostaglandin E2 an important player in cancer.But it can also affect a particular type of immune cell, called a T cell, by effectively ‘putting it to sleep’. This is an important safety mechanism that ensures the immune response doesn’t spiral out of control, which can lead to disastrous consequences.
Prostaglandin E2 is made by molecular machines in cells called cyclo-oxygenase 1 and 2, or COX-1 and COX-2 for short. And there’s already evidence that levels of COX are unusually high in several types of cancer, including bowel, breast and lung.
So Professor Reis e Sousa and his team set about investigating whether prostaglandin E2 or COX-1 and 2 could be possible targets for treating cancer.
Dampening down the immune response
Their latest research focuses on lab-grown melanoma skin cancer cells, originally taken from mice that were genetically prone to developing the disease, thanks to a fault in a gene called BRAF.
By testing the chemicals released into the nutrient broth the cancer cells were growing in, the team found that they were producing something that was able to stop immune cells from reacting to the ‘danger’ signals that normally trigger them into action. Could this mystery molecule be prostaglandin E2?
Using an exciting new genetic engineering technique called CRISPR, the researchers deliberately ‘edited out’ the COX-1 and COX-2 genes in the melanoma cells, meaning they could no longer make prostaglandin E2. And – just as they suspected – the cancer cells lost their ability to damp down the immune response.
Next, the researchers compared mice transplanted with ‘normal’ skin cancer cells to mice whose melanoma cells lacked COX-1 and -2 genes, and they spotted two important things.
Firstly, animals with tumours lacking COX-1 and -2 (so were unable to produce prostaglandin E2), had a much stronger immune reaction to the cancer cells. And secondly, this reaction meant that the tumours with missing COX genes could now be attacked by immune cells, unlike cancers with normal COX genes.
Excitingly, the scientists saw a similar pattern when they repeated the experiments with bowel and breast cancer cells, implicating prostaglandin E2 in the growth of these types of cancer too.
An aspirin boost
You might reach for the aspirin when you have a fever, but what you might not realise is that aspirin works by targeting COX-1 and 2. So Professor Reis e Sousa wondered whether aspirin might be able to mimic the effects of knocking out the COX genes, reducing prostaglandin E2 levels and helping to drive a stronger immune response against the mice’s tumours. Just as they’d seen in their genetic engineering experiments.
To test this idea, the researchers added aspirin to the drinking water of mice transplanted with melanoma cells.
By itself, the drug had no effect – this isn’t surprising, as there’s no evidence that aspirin alone can treat cancer. But when they combined it with a new class of immunotherapy treatment known as a checkpoint inhibitor, which helps to ‘unmask’ tumors so they can be targeted by the immune system, they saw something remarkable.
Mice given aspirin along with the immunotherapy drug got rid of their tumors much more quickly than those receiving immunotherapy alone. Even more excitingly, the animals became ‘cancer-proof’: they developed a strong immune ‘memory’, and their immune cells recognised and immediately destroyed the same type of cancer cells, even months after the first experiment.
The scientists saw the same immunotherapy-boosting power of aspirin when mice were transplanted with bowel cancer cells: even though the immunotherapy didn’t have much effect by itself, the tumors shrank significantly in around a third of the animals treated with the combination.
