Gut bacteria affect cancer immunotherapy outcome
Whether a cancer patient responds to certain treatments is dictated by the bacteria they carry in their intestines, US scientists have discovered.
Cancer cells have damaged DNA, which causes them to disobey the normal rules and controls that govern their growth and behaviour. This means that they can invade adjacent tissues, spread through the bloodstream to other organs, and also upset the body's biochemistry by secreting chemical factors and hormones.
Tumour cells can also manipulate the immune system, often by over-producing chemical "off" switches that prevent the cancer cells being recognised, attacked and removed. In recent years this discovery has led to the birth of "immunotherapy" where tailor-made antibodies or other molecules are administered to block these off signals, one of which is called PD-1, and encourage the immune system to move in.
Some patients respond extremely favourably to these approaches while others do less well, although it wasn't clear why. Now University of Texas researcher Deepak Gopalakrishnan and his colleagues think they know the answer: differences in the combinations of intestinal bacteria carried by patients can affect their responses to immunotherapy.
Writing in Science this week, the Texas-based team have analysed faecal samples from over 100 malignant melanoma patients who were undergoing immunotherapy with a PD-1-blocking drug. The researchers divided the patients into two groups - those that responded well to the immunotherapy, and those that did not - and compared the relative proportions and the diversity of the patients' intestinal bacteria.
Responders, they found, had a significantly greater diversity of gut bacteria compared with the non-responders and also showed specific enrichment of several bacterial groups including the Clostridiales, Faecalibacterium species and Ruminococcus bacteria. Immunotherapy non-responders, on the other hand, had relatively higher levels of Bacteroides bacteria. These differences were also echoed in the patients' tumours, where the responders had higher levels of inflammatory signals and more immune cells infiltrating their cancers. The non-reponders showed fewer immune cells in their tumours overall, and a higher proportion were regulatory cells, called "Tregs", which damp-down immunity.
But are these differences in the intestinal microbes contributing to the immunotherapy response, or merely a side-effect of it? To find out the team took groups of mice with tumours and colonised the animals with gut bacteria from either human immunotherapy responders or non-responders. Tumours in the mice receiving bacteria from the human responders progressed significantly more slowly compared with animals colonised with bacteria from human non-responders.
"Signals from bacteria in the intestine are in some way manipulating immunity around the whole body," explains Jennifer Wargo, who led the research team. "Interactions between the intestinal bacteria and immune cells are constantly shaping the immune response. So having the right spectrum of bacteria there primes the immune system to be better able to attack a tumour if given the chance..."
So could altering the composition of a patient's intestinal microbiome be used, in future, to improve cancer treatment outcomes?
"Absolutely we think it could!," says Wargo. "The concept for treating cancer patients with a faecal transplant to improve therapeutic response is very real and, in fact, we're currently planning a study to do just that..."