What’s that smell? It’s just your personal community of microbes, living in you intestines and helping you digest your food. Other than producing socially unacceptable gaseous emissions, researchers have been finding that the population of bacteria residing in your innards (aka the human microbiota) also influences other bodily processes such as immunity and your brain’s response to stress. A recent paper by Goldszmid’s research group at the National Cancer Institute is now finding that gut microbes may also influence a cancer tumor’s response to therapy via its effect on the immune system. Previous cancer studies have found that the immune cells can be both beneficial and harmful in the treatment of cancer, its role depending on the type of cancer and cancer therapy used. In a related field, researchers have discovered gut bacteria are essential to the full maturation/function of gut immune cell activity. This study by Iida et al. now links the two concepts and shows that the gut microbiota is essential for the effectiveness of cancer therapy in specific cancer treatment scenarios. These finding highlight the importance of strategic planning of a patient’s cancer treatment which may include modulating the immune system in the near future.
For the past decade, scientists are finding that the state of the immune system can interact with other aspects of biology, which can have disadvantageous outcomes: exacerbating type II diabetes and even contributing to the cause of certain cancers. On the flip side, the immune system is critical in keeping our bodies infection free and even helping cancer therapies eliminate malignant cells. In fact, a class of cancer therapeutics, called immunotherapies, aim to harness the destructive power of the immune system to target cancer cells. In addition, some cytotoxic chemotherapies (drugs that are toxic to all dividing cells) utilize immune cells to injure and kill cancer cells. For example, breast cancer patients who carry mutations in a gene important for the full activation of the immune system (Toll-like Receptor 4) relapsed more quickly after chemo- and radiation therapy than those who do not. Given this emerging knowledge, considering a patient’s immune system biology may become a part of the development of personalized medicine.
Unsurprisingly, the large amount of bacteria colonizing your digestive tract influences the state of your immune system. Who can blame them for moving in? It’s cozy, warm and nutrients are delivered on a daily basis (hopefully). Hundreds of different bacterial species find their own niche by consuming specific materials, which can range from your indigestible food (cellulose from plants) to by-products of other bacteria’s activities. Don’t worry, this relationship is not one-sided. In addition to helping humans maximize digestion, commensal bacteria help the host keep pathogenic bacteria out in three ways: 1) by competing for limited nutrients, 2) by stimulating the mucosal barrier between the intestinal tissue and bacteria, and 3) by priming the host’s immune system. These friendly bacteria are actually necessary for the optimum immune activity in your intestines – a place that constantly encounters foreign material. Animal experiments have shown that in the absence of gut bacteria, achieved through use of antibiotics or raising mice in a completely sterile environment, result in a thinner protective mucosal barrier, decreased presence of gut immune cells and increased susceptibility to pathogenic infection. The state of gut bacteria can promote immunity and in the case of certain cancer therapy scenarios, Goldszmid’s group has found it beneficial.
Iida et al. investigated the contribution of gut bacteria to chemotherapy response using a mouse tumor model system. Mice bearing lymphoma, colon and melanoma tumors were pre-treated with a three week course of antibiotics and then given one of two types of cancer treatment: 1) an immunotherapy cocktail that stimulates innate immune cell activation, or 2) a traditional cytotoxic chemotherapy (oxaliplatin) that causes DNA damage in dividing cells. Both treatments were less effective when the mice microbiota were abolished with either anti-biotic pretreatment or raising the mice in a germ free environment. The scientist then investigated the state of immune function in the antibiotic treated mice and found that expression of a cytokine that triggers cell death (Tumor Necrosis Factor or TNF) was overall reduced in tumors and that the presence innate immune cells capable of secreting TNF were reduced inside tumors as well. Interestingly, the tumor response to both cancer therapies were restored in antibiotic treated mice with two different methods: 1) dosing with an especially immune reactive bacteria (Alistipes Shahii), 2) dosing with a bacterial protein that illicits a strong immune response (Lipopolysaccharide). The study neatly links the presence of microbiota, the immunological state and the effectiveness of some cancer treatments.
- Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science (New York, N.Y.) 342, 967–70 (2013).
- Kamada, N., Seo, S.-U., Chen, G. & Núñez, G. Role of the gut microbiota in immunity and inflammatory disease. Nature reviews. Immunology 13, 321–35 (2013).
- Grivennikov, S., Greten, F. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–99 (2010).
- Apetoh, L. et al. Toll-like receptor 4 – dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Medicine 13, 1050-1059 (2007).