We tend to think of our immune system as the ‘police force’ of the body, protecting us against illegal aliens such as bacteria and viruses. It can also help protect us from cancer by rounding up errant and misbehaving cells before they can grow into tumours.
But, as we’ve previously discussed, under different circumstances it can also play an important role in the development of cancer too, by switching on uncontrolled inflammation.
In fact, just as cops can become corrupted and allow crime to flourish, immune cells called macrophages – which normally help to protect us against disease by gobbling up invaders and dead or dying cells – can switch sides in the fight against cancer, blocking the effect of chemotherapy on tumours.
New research, published in the Journal of Clinical Investigation, reveals more about this complex battle between the immune system and cancer, and further highlights the role of macrophages.
Let’s look in more depth at what the scientists did and what they found.
Delving into drug resistance
Working together with colleagues in Italy, Professor Gillian Tozer and Professor Claire Lewis (both based at the University of Sheffield and funded by Cancer Research UK) wanted to understand why a new cancer drug wasn’t working as well as expected.
The drug, called combretastatin, is currently being tested in early-stage clinical trials for a range of different types of cancer. It’s supposed to work by interfering with the blood vessels that feed tumours, shutting off their blood supply and making them shrink and die.
Tests have shown that the drug can be very effective initially, but cancers eventually develop resistance to the treatment – the effects wear off and tumours start growing again.
To understand why this happens, the researchers studied mice with breast cancer that had been treated with combretastatin. As expected, just 24 hours after treatment with the drug, tumours were showing signs that their blood supply was being shut down.
But when the scientists looked more closely at these tumours, they discovered something rather unwelcome – they were surrounded by large numbers of macrophages.
Unfortunately, these weren’t “good cop” disease-fighting macrophages. Instead they were behaving like “bad cops”, pumping out molecules that directly counteracted the effects of combretastatin treatment by encouraging the growth of new blood vessels into the tumour.
Spotting the signals
But how were these macrophages being summoned to the tumours? To find out, the researchers analysed the levels of certain chemical signals produced by both the tumour cells and the cells directly surrounding them.
One signal in particular stood out. Professor Lewis and her team noticed particularly high levels of a molecule called CXCL12 in and around tumours. This chemical normally helps blood vessels to grow, but it also strongly attracts macrophages.
The researchers figured that treating tumours with combretastatin was somehow switching on the production of CXCL12, attracting misbehaving macrophages that combat the effects of the drug by encouraging the growth of new blood vessels. But what could be done to fight this corruption?
Turning the tables
CXCL12 attracts macrophages because they have specialised ‘receiver’ molecules on their surface that recognise the signal. The Sheffield team discovered that blocking these receivers with a drug called AMD-3100 (also known as Plerixafor) increased the effectiveness of combretastatin treatment, providing more evidence that CXCL12 was indeed responsible for summoning macrophages to tumours.
To prove that it was definitely the macrophages stopping combretastatin from working, the scientists tested mice lacking those particular immune cells. They found that combretastatin was significantly more effective at combating breast tumours in these animals, causing cancer cells to die off in large numbers.
The results from Professors Lewis and Tozer provide us with two important pieces of information.
Firstly, we now know that a rush of macrophages into tumours can hamper the effectiveness of combretastatin. This explains – at least in part – why the drug hasn’t lived up to its promise in clinical trials.
And secondly, blocking the signals that attract these cells can significantly increase the potency of the drug. Although this knowledge is important, it’s not yet at a stage where it can be used to treat cancer patients. However, there’s a lot of promise for the future.
Combretastatin is currently being tested in early-stage clinical trials in people with cancer, and it’s not yet known how effective it is at treating the disease. But the new research certainly suggests that combretastatin and Plerixafor (or similar drugs) might be a winning combination for treating at least some forms of cancer, although this idea will need further testing in the lab and clinical trials.
What’s also interesting is that a research group in the US made a similar discovery last month, showing that an influx of immune cells into tumours can make them resistant to the chemotherapy drug paclitaxel (Taxol).
It’s becoming increasingly clear that the transformation of immune cells from ‘good cop’ to ‘bad cop’ is a major factor in the growth of cancer and its resistance to treatment. So finding ways to combat this corruption within the immune system could lead to powerful new approaches to cancer treatment in the future.
Welford AF et al (2011). TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. The Journal of clinical investigation PMID: 21490397