Role of the microbiota in regulating the mononuclear phagocyte system

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Mononuclear Phagocytes (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. We have previously 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 demonstrated 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 remain unknown. In our most recent work, we identified a mechanism by which microbiota programs the antitumor activity of MPs in the tumor microenvironment. This mechanism can be triggered by a high-fiber diet, which potentiates antitumor immunity and enhances response to immune checkpoint blockade (ICB) (Cell 2021; Oct 14;184(21):5338-5356). In parallel studies, we also revealed a previously unrecognized role of vitamin D in promoting tumor control and ICB response through a microbiota-dependent mechanism (Science 2024 Apr 26;384(6694):428-437). Brain metastases (BrM) are a serious event for many cancer patients, including melanoma, improved therapeutic strategies remain a clinical imperative. While ICB has shown promising results, the regimens for optimal efficacy of ICB in BrM are yet to be determined. Furthermore, a comprehensive characterization of immune populations in the BrM TME, needed for identifying potential new targets, is lacking. We developed two new clinically relevant models of melanoma BrM representing human disease. These models display distinct responses to ICB as observed in the clinic. We performed and in-depth characterization of their immune infiltrate and identified potential correlates of ICB response (Daugherty-Lopès et al., bioRxiv 2024). We further developed a new semi-automatic machine-learning approach to accurately assess BrM burden on whole-brain stereomicroscope images (Rappaport et al., Methods Cell Biol. 2024).