Role of the microbiota in regulating the mononuclear phagocyte system

Division Of Basic Sciences - Nci

Investigators

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Abstract

Mononuclear phagocytes MPs play crucial roles in the initiation of innate and adaptive immune responses and in the maintenance of tissue homeostasis. Although MPs share several phenotypic and functional characteristics, it has recently become clear that dendritic cells (DC), macrophages (Mac) and monocytes (Mo) are not homogeneous populations and instead they represent developmentally and functionally distinct populations that differentially regulate T cell function. MPs are major components of the tumor microenvironment where they play a dual role inducing adaptive anti-tumor responses but also sustaining immune evasion, tumor progression, and metastasis formation. Despite major advances in the identification of the MPs developmental pathways and their transcriptional regulation, the individual contribution of these distinct cell subsets to the induction and resolution of immunity against invading pathogens, or to anti-tumor responses or immune evasion, as well as the environmental signals involved in their regulation remain unclear. In this project we will use murine experimental tumor models to investigate the mechanisms regulating MP differentiation and function, with particular emphasis on the role of the commensal microbiota. Local and systemic inflammation modulates cancer susceptibility (e.g. in obesity), cancer progression, response to therapy, and co-morbidity (e.g. cancer cachexia/anorexia). The microbiota influences both immune and metabolic function beyond the gut, including peripheral innate cell responses, autoimmunity and response to viral infections. In recent studies we have shown that gut commensals control the response of subcutaneous tumors to immunotherapy and chemotherapy by modulating tumor infiltrating MP function (Science 2013, 342:967-970). This study demonstrates the novel finding that and intact gut microbiota is needed for optimal response to cancer therapy and underscores the potential to improve cancer treatment by manipulating the gut microbiota. However, the exact molecular mechanisms by which commensal bacteria modulate systemic inflammation are still unknown. We use several approaches to address this question performing parallel studies in cancer and infection models. We utilize the germ-free (GF) facility at NCI-Frederick to compare conventionally reared, GF animals, or animals treated with different antibiotics or given different diets to modulate the microbiota composition either under steady state or different inflammatory settings. We have characterized the innate myeloid and lymphoid infiltrate in several tumor models in the presence or absence of intact microbiota. Our results showed that in the absence of an intact microbiota there is a skewing of myeloid cell differentiation towards a pro-tumoral phenotype. We have shown that these changes occur specifically in the tumor and are not observed in the bone marrow, blood or peripheral lymphoid tissues. Importantly, we have identified the cellular and molecular pathways involved and we have shown that dietary manipulation of the microbiota can trigger the same pathways to improve anti-cancer immunity. We are currently extending these studies to interrogate the role of microbiota in metastasis formation. In parallel studies, we are dissecting the role that individual myeloid cell population play in response to cancer therapy. We demonstrated that neutrophils are required for the optimal response to chemotherapy, showed that tumor-infiltrating neutrophils are highly heterogeneous and phenotypically and functionally distinct from circulating neutrophils. We have also shown that microbiota-derived signals regulate neutrophil dynamics in the TME and we have identified a clinically relevant bacterial-derived molecule capable of restoring neutrophils function in microbiota-depleted animals. In a different set of studies, we are addressing the role of different myeloid cell populations in tumor progression. In particular, we are studying the dynamics of the monocyte/macrophage compartment during chronic inflammatory conditions and how they impact tumor growth.