Gut microbes communicate in bidirectional way with the brain, with mechanisms that involve the hypothalamic-pituitary-adrenal axis, several neurotransmitters, and microbial metabolites. Immune system lies at the interface among the two systems, mediating part of the effects of microbe-released factors on brain functions. Microbial composition of the gut is influenced by a variety of issues including diet, environmental factors and antibiotic use. The same factors play key roles in brain functions, modulating plasticity processes via modification of brain microenvironment. Recent evidence demonstrate that gut-resident microbes may modulate tumor microenvironment, with efffects on therapy efficacy.
We have recently demonstrated that, in mouse models of brain tumor, the housing conditions modulate brain tumor microenvironment, both with immune and non immune mechanisms.
In this project we want to verify the hypothesis that gut microbes signal to the brain, modifying brain tumor microenvironment and that these signals are integrated with those coming from the external environment, affecting innate immune system activation, and contributing to regulate brain tumor growth.
Patients with brain tumors, and in particular those with glioblastoma (GBM), do not have efficacious therapeutic options and, consequently, there is a large unmet need for new combinatorial approaches.
The study of how microbes and the microbiota may contribute to cancer development and progression recently emerged as an area of intense research. Several evidence demonstrated that microbiota, and in particular gut microbiota, may modulate patient response to specific cancer therapies and mitigate some of their adverse effects (20). The increased knowledge of how host genetics, interacting with signals coming from the environment, life style and diet, led to the definition of a tumor microenvironment, opens new perspectives for cancer prevention and treatment. The proposed project, investigating the mechanisms of bidirectional communication between microbiota, the environment and GBM, and the intermediate role played by the immune system, will shed light on the possible therapeutic targeting of members of this pathway. In fact, immunotherapy of GBM is recently emerging as a new possible therapeutic treatment, and a wide array of immunotherapeutic interventions are currently being tested in glioma patients, with some encouraging results (21). The main objective of our study is the identification of the molecular and cellular targets that could revert the vicious cycle occurring among brain tumor cells, microglia and infiltrating immune cells that, creating an immunosuppressive environment, restrain the host response against tumoral cells. We believe that this study will decifer the potential effects of environmental signals on brain tumors, thus offering new therapeutic perspectives to re-educate the host immune system in preclinical models of GBM, with possible identification of future translational, proof of concept results.
20 Garrett WS. Cancer and the microbiota. Science 2015; 348(6230):80-6. doi: 10.1126/science.aaa4972.
21. Brown CE, et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med. 2016; 375(26):2561-9. doi: 10.1056/NEJMoa1610497.