Every person has about as many bacterial cells in their body as human cells (about 30 trillion of each!). These bacteria—the microbiota—play roles in a wide variety of bodily processes. This includes digestion (not unexpected, given that most of the microbiome is in the gut), but also impacts other organs, including the heart and the respiratory tract, and systemic diseases, including obesity and diabetes. The microbiota also has a crucial impact on the immune system. The microbiome has been shown to promote tissue homeostasis through induction of a protective/tolorigenic immune microenvironment and control against external pathogens such as C. difficile and influenza. However, one of the most surprising roles of the microbiome is its control of patients’ responses to cancer therapies—both chemotherapy and immunotherapy—through effects on the immune system.
Cyclophosphamide is a chemotherapeutic drug used to treat a variety of cancers, including lymphoma, leukemia, prostate cancer, renal cancer, and thyroid cancer. The mechanism of action of this treatment induces immunogenic cell death, induction of Type I interferon, activation of antigen-presenting dendritic cells, promotion of Th1/Th17 immune responses, and a proportional decrease of immunosuppressive T cell populations. The microbiome is required for this effect. Specifically, Gram+ bacteria are required for the induction of Th1/Th17 immune responses following cyclophosphamide treatment. Cyclophosphamide induces permeability of the intestinal wall, allowing lactobacilli and enterococci to translocate from the small intestine to the spleen and mesenteric lymph nodes. Once in the secondary lymphoid organs, these bacteria induce the differentiation of Tbet- and IFNg-producing T cells of both the Th1 and so-called pathogenic Th17 subtypes. Using models of germ-free mice, mice treated with broad spectrum antibiotics to obliterate the microbiome, or mice treated with an antibiotic that specifically depletes Gram+ bacteria, treatment of tumor-bearing mice with cyclophosphamide led to a reduced effect on the delay of tumor progression compared to wild-type mice. The anti-tumor efficicacy of cyclophosphamide treatment was dependent upon the development of pathogenic Th17 cells and tumor-infiltrating antigen-specific Type-1 T cells.
The anti-CTLA-4 antibody known as ipilimumab is FDA approved to treat melanoma, and is in clinical trials for other cancers. CTLA-4 is a negative regulator of T cell activity; blockade of CTLA-4 blocks its T cell-suppressive effects and induces an anti-tumor immune response through direct activation of T cells. The composition of the microbiome affects both the response to this therapy and the potential side effects that a patient can suffer as a result of treatment. In mouse models of sarcoma, melanoma, and colon carcinoma, response to an anti-CTLA-4 therapy depends on particular intestinal microbiota, specifically of specific Bacteroides species. The presence of these bacteria induces an anti-bacterial Th1 immune response, which correlates with delayed tumor growth. This response translates into humans, where anti-Bacteroides Type-1-polarized immune cells can be found in peripheral blood taken from metastatic melanoma or non-small cell lung cancer patients treated with ipilimumab; this inversely correlates with tumor size.
The same group indicated that in a mouse model, Bacteroides are protective against anti-CTLA-4-induced colitis, a common side effect of this therapy that results in morphological changes in the gut and related weight loss. Expanding upon these results, it was additionally shown that the presence of Bacteroides in patient microbiota can be used to predict their likelihood of developing treatment-induced colitis. Patients with higher frequencies of Bacteroides in faecal samples taken prior to the induction of treatment were more likely to be colits-free after treatment with ipilimumab.
This phenomena is not limited to anti-CTLA-4 immunotherapy. As shown in mouse models of melanoma and bladder cancer, the efficacy of anti-PD-L1 therapy is dependent upon Bifidobacterium via an indirect effect on CD8+ T cells.
While the effects of the microbiome on the efficacy of cancer therapeutics have largely been studied in mouse models, studies of the human microbiome in other diseases has provided a basis for translating these results. Profiling the bacterial species in a specific patient’s microbiome can provide clues regarding an individual’s response to a particular therapy, as shown already with Bacteroides and resistance to CTLA-4-induced colitis. It may also direct a patient towards a therapeutic that may be more effective, or towards a therapy to repopulate their gut with bacterial species that will support the treatment they are receiving. Integrating the profile of an individual’s gut microbiome should be further evaluated as a tool to improve responses to treatment based on the interaction of a therapeutic intervention and specific bacterial species.
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