Inflammation is the body’s first line of defence against insult. Without inflammation, most of us would not make it past the first year of life. This rapid reaction force fights infections, heals wounds and helps our more sophisticated adaptive immune system generate a longer-lasting specific response. But there is a downside to this powerful response; sometimes inflammation fails to resolve. Indeed, chronic and often low-level inflammation underlies many of the diseases of middle and old age: cardiovascular disease, diabetes, arthritis, dementia – and cancer.
If genetic damage is the match that lights the cancer fire, inflammation is the fuel that feeds the flames. There are multiple lines of evidence that support this idea. Some chronic inflammatory diseases increase the risk of developing a cancer – for instance hepatitis, inflammatory bowel disease and pancreatitis. Cancer can also cause inflammation – genetic damage to a cell with malignant potential attracts inflammatory cells that begin to fuel the cancer flames. Cancers are not just masses of malignant cells but complex ‘rogue organs’ where normal cells are recruited and corrupted to help the cancer grow and spread. This rogue organ is known as the tumour microenvironment and is usually abundant in inflammatory cells and molecules.
As chronic low level inflammation promotes cancer, are anti-inflammatory drugs useful in cancer prevention and treatment? Over the past twenty years or so experiments in many different mouse models of cancer clearly showed that targeting inflammatory cells or molecules could slow down cancer growth and spread, and if this was done in the earliest stages, cancers could be prevented. The latter finding was replicated in clinical trial of people taking aspirin to prevent cardiovascular disease. These trials, carried out on tens of thousands of people over 10 years or more, show that aspirin reduces the development and spread of certain cancers. However, it is not clear if aspirin benefits all people: the risk of stomach bleeding is increased for instance, and there may be no effect in older people (70+). More research is certainly needed to understand the cancer-preventative actions of this oldest of drugs.
An exciting discovery
Another more recent clinical trial has excited those of us working on cancer and inflammation. A molecule called interleukin-1 beta (we’ll call it IL-1) is one of the major players in human inflammation. Having evidence that IL-1 might contribute to heart disease, Paul Ridker and colleagues in Boston USA treated patients who were at high risk with a drug that blocked IL-1. Their hypothesis was proven: those receiving the IL-1 blocker suffered less heart disease, but, unexpectedly, patients also developed less cancers, especially lung cancer (many of these patients were smokers). We think that this group of patients already had small lung cancers, because of their smoking history, and the IL-1 blockers stopped progression to detectable malignancy. Again, more clinical trials and lab research are needed but this is a promising finding, especially as the IL-1 trial involved 10,000 individuals.
At the moment, anti-inflammatory treatments do not seem to work in advanced human cancers, but over the past 10 years or so rapid advances in immunotherapy have taught us that we can harness the power of the more specific and sophisticated adaptive immune system to fight cancer, even when the cancer is in its final and most lethal stages.
Treatments that involve the adjustment of the immune system’s response to cancer and/or the use of CAR T cells – modified human immune cells – stimulate killer T immune cells to recognise and destroy malignant cells, sometimes with such long term beneficial effects that the word ‘CURE’ is appropriate. But these exciting responses only happen with some cancers and some patients. This is where cancer and inflammation research may be able to help. Inflammatory immune cells such as macrophages are abundant in cancers and there is increasing evidence that these cells can be highly immune-suppressive. New treatments that combine immunotherapy with anti-inflammatory strategies hold promise for the future.
One approach is to target macrophages – a type of blood cell involved in the immune system - just before using treatments that ‘wake up’ the T cells. Another is to ‘re-educate’ the multitude of macrophages that surround malignant cells. Like T cells, macrophages can recognise and kill malignant cells but in the tumour microenvironment their behaviour is radically altered – they have acquired a number of functions that help the malignant cells survive and spread. Now we have experimental treatments that can switch these ‘bad’ cancer-promoting macrophages to ‘good’ cancer-killing macrophages – essentially waking up a dis-functional army of inflammatory immune cells into an effective fighting force.
Although we understand a great deal about cancer-related inflammation, there is more to learn, especially about what happens in human cancers. This is the focus of my research. With funding from the European Research Council and Cancer Research UK, my lab has been developing new models of the tumour microenvironment. As I will describe in the Ideas Lab session, I have been using tissue engineering techniques to grow mini-human tumours in the lab. These are made from multiple human cell types, including inflammatory cells, that grow together in a 3D artificial tumour microenvironment. Other models, in mice, carefully reproduce the genetic mutations and location of the human disease.
Our aim is to use these models find the best way of reducing the chronic inflammation of cancer so that the undoubted power of the immune system can be unlocked to attack and destroy cancerous cells and their dangerous tumour microenvironment.