World Oncology Forum 2015
The impact of microbiota on the immune response
Dr Giorgio Trinchieri - Center for Cancer Research, Bethesda, USA
We try to understand the role of inflammation with cancer initiation and progression. Recently we became very interested in the aspect of the microbiota, that means the common cell micro-organisms, like bacteria and others, that live in our body and on the surface of our body. They regulate many functions of our body, including inflammation and directly and indirectly they have an effect on cancer.
How do they influence inflammation?
There are many studies ongoing on that. Not everything is very clear but when they are present on all the various surfaces of our organs, these are surfaces like the skin, the gastrointestinal tract, or the lung, for example, or the mouth, or the lung, so this barrier with the outside of the organism. They are in direct contact with the epithelium so they may form substances and products, toxins may even be normal parts of them that are recognised, the organisms react against them and the organisms can react with inflammation but because these are really common cells the body tries not to respond to them. So in normal conditions the body muffles the inflammation, tries not to induce inflammation. So there is a mechanism not to respond with inflammation.
But there are cases in which, for example with organs, they are pathogenic, they induce disease. They are recognised and the body responds with an inflammation immune response. When the composition of these microbes, there are hundreds of thousands of different microbes, different species of microbes live in our body, when the composition change or the characteristics of these microbes change, which is called dysbiosis, the organisms can respond in different ways, can respond with an inflammation. This happens at the barrier but there are also mechanisms by which the signal at the barrier, for example from our skin or our gut or intestine, get transmitted in a systemic level. They really affect the inflammatory tone, immunity and metabolism and other functions all across the different organs in the organism. So they can affect cancer in this way in any place in any organs of the body.
What role might fungus play?
When we think about microbiota we tend to think about microbes but microbes have their own virus, the phage, then there are many viruses that are also common cells, there are even viruses that are present in our own genome, that virus infection happened a long, long time ago but they are still maintained in our genome. There are fungi and all of these, when there is an alteration in the immune response, especially where there is bacteria dysbiosis, this fungal infection can be present, certain virus infections can be present and by themselves or together with the bacteria they can affect inflammation.
In addition to that, several viruses have a direct oncogenic effect, they can induce mutations in the cells – infect the cell, induce mutation. The typical example is human papilloma virus for cervical cancer, for example. But the way they infect cells, the way they affect inflammation, is always modulated by a balance with the different components of the microbiota. So even in the case of cancer induced by virus or by fungi, the common cell microbiota can play a role because it cooperates with this type of interaction.
Can microbiota influence the response to chemotherapy?
That’s what we, and other groups, have found recently and many types of cancer therapy involve an aspect of metabolism inflammation. So we have found, and there are many recent studies of immunotherapy, the type of therapy that tries to induce an immune response against the tumour, that are strongly affected by the microbiota. That is again, in part at least, by the role of microbiota in regulating the inflammatory tone. Even chemotherapy, normally we think about chemotherapy just as a chemical substance that has a toxic effect on cells, particularly on the DNA in the cell, inducing cell death, but even chemotherapy in order to be able to induce cell death requires certain components of inflammation, for example the production of species of oxygen that are needed for the chemotherapy to induce this type of damage.
It has also been proposed recently that the way the chemotherapy induces a profound effect against cancer is by killing some of the cancer cells and exposing them to the immune system and inducing an immune response that eventually can eliminate more completely the cancer. This type of immune response, as all the immune responses in the body, can be modulated by the composition of the microbiota. So this is another way in which the microbiota affect chemotherapy.
What about the role of antibiotics?
We use antibiotics as the first way to show that when we eliminate microbiota we don’t see certain of the effects of the microbiota, for example, on cancer therapy. The important thing to keep in mind is that even when we remove the antibiotics, especially when we induce a profound reduction in the microbiota, the microbiota really never goes back to what was before. Not all the same species come back and in general the number of species is lower, it’s what’s called the diversity of the microbiota. So even when we use antibiotics for therapeutics, especially in children they use antibiotics, several cycles of antibiotics, in a few years a change in microbiota is induced by this treatment that may or may not be damaging for the organism but can be damaging. For example, it has been shown that antibiotic treatment in kids can increase quite dramatically the incidence of inflammatory bowel disease because of the change in the microbiota. And in particular in cancer, for example in bone marrow transplantation, especially for hematopoietic cancer, the patients before the transplantation are treated with chemotherapy and with antibiotics in order to avoid some of the toxic effects of chemotherapy. This induces a decreased diversity in the microbiota of the patient and the group at Palmer and others have clearly showed that patients with a very decreased diversity in the microbiota survive significantly less than the patients that maintain a diversity. So that shows the important role of the diversity of the microbiota but also shows the possibility that it’s possible to intervene and try to main a diversity of microbiota in the patient and hopefully have an effect on survival.
Do antibiotics complement other therapies?
It’s impossible not to give antibiotics, obviously we know the reason that we live to be 80 or 100 these days in comparison with 50 years ago is because of the antibiotics and being able to fight infection, disease; chemotherapy induced immunosuppression without antibiotics would be almost impossible to treat the patient. So we cannot avoid giving antibiotics. The possibility is trying to find a way to change the composition of microbiota or to correct the composition of microbiota. The simplest way has been used in certain infections, for example the intestine infection Clostridium difficile, that is always associated with dysbiosis, a change in microbiota, is to give a transplant from normal microbiota from a healthy individual and provide that and try to reconstitute the microbiota in the patient. In the case of Clostridium difficile infection that is about 95% effective and is effective within a few days because the microbiota get changed immediately.
Much more complicated is trying to increase the diversity in the patients being treated or to try to modify the microbiota, the balance of the different species of microbiota to be the species that are favourable for what we want to obtain and avoid the species that can be damaging. That’s more complicated in a way, one could use selective antibiotics, there are specific therapies that can directly affect certain species and not other species, or we can provide some species and try to increase the number of certain species in the microbiota. There’s still a long way to go, it’s still a future therapy, but I think the technology is there or will be there soon.
