Elliott, Michael R.
Associate Professor, Microbiology, Immunology, and Cancer Biology
- BS, Biology, Wake Forest University
- PhD, Microbiology and Immunology, Wake Forest University School of Medicine
Cancer Biology, Cell and Developmental Biology, Immunology, Microbiology, Molecular Biology
Macrophage effector functions in inflammation and immunotherapy
The research focus in the Elliott Lab is to understand the function of tissue-resident macrophages as effectors of innate immunity in acute and chronic inflammation, and cancer. Macrophages are a phenotypically diverse, multifunctional population of immune cells found in every tissue in the body that play key roles in maintaining normal tissue function and immune defense against pathogens. Our work focuses on defining the molecular pathways that regulate macrophage motility, phagocytosis and inflammatory responses related to their roles in the clearance of dying cells and cancer cells. We use a wide range of advanced genetic, biochemical, transcriptomics, and imaging techniques to address these questions. Through ongoing collaborations with multiple basic and clinical research labs, we ultimately seek to translate our research efforts into new disease therapies that harness the powerful immune-regulating properties of macrophages.
Project Area 1: Macrophage Phagocytosis in Cancer.
Macrophages are now established as a key cell type in the regulation of cellular transformation, tumorigenesis, and anti-tumor immune therapies. As such, there is increasing interest in translating our understanding of macrophages into effective anti-cancer therapies. Through collaborations with multiple clinicians, my lab has established two distinct projects that leverage our expertise in myeloid and macrophage biology to investigate novel roles for macrophages in hematologic malignancies: 1) Understand the mechanisms that regulate the rate and capacity of macrophages to engulf and kill malignant cells targeted by therapeutic monoclonal antibodies (mAbs). mAbs can be highly effective at reducing tumor burden, and one of the main mechanisms by which mAbs kill tumor cells is via antibody-dependent cellular phagocytosis (ADCP) mediated by tissue macrophages. While mAbs can be very effective, as monotherapies these mAbs are not curative, but the reasons for this are poorly understood. Recently, we discovered that macrophages have a finite capacity to engulf mAb-opsonized tumor cells and that this limitation could be a novel factor in therapeutic resistance to mAb therapies for many types of cancers (Pinney et al. 2020. Blood). Our efforts to understand the mechanisms that regulate macrophage phagocytic capacity will lead to improved therapeutic application of mAbs in many diseases. 2) In a second project, we are carrying out detailed phenotyping and functional analyses of macrophage populations in the bone marrow and using this information to understand the specific roles of these macrophages in controlling inflammation that contributes to age-related marrow failure diseases and hematologic malignancies in preclinical mouse models (Frisch et al. 2019. JCI Insights).
Project Area 2: Role of Macrophages in the Resolution of Tissue Inflammation.
Macrophages are central regulators of inflammation and tissue repair. We recently discovered a novel role for the anti-inflammatory ecto-enzyme CD73 on macrophages in regulating the resolution and repair of tissues following inflammation (Murphy et al. 2017. Cell Death Diff.). CD73 is the rate-limiting enzyme involved in the generation of extracellular adenosine a powerful anti-inflammatory mediator that suppresses the function of numerous innate and adaptive immune cell populations. The current focus of our work on CD73 is centered on understanding the role of CD73 in regulating macrophage-mediated inflammation in the contexts of aging (or inflammaging) in the lung, marrow, and peritoneum and in hematopoietic cell dysfunction. There is growing interest in CD73 as a therapeutic target for the treatment of numerous types of cancer. As such, our work will provide novel insights into the specific role of CD73 on macrophages in regulating tissue inflammation homeostatically and in disease settings, including cancer.
Project Area 3: Bone Marrow Macrophage Regulation of Erythropoiesis.
Anemia is a massive worldwide source of disability, afflicting one third of the worlds population. Erythroid-associated macrophages (EA-Macs) provide a fundamental phagocytic function in hematopoietic organs through the clearance of extruded nuclei (called pyrenocytes) from reticulocytes in the terminal stages of erythropoiesis. In collaboration with the Palis Lab (U. Rochester), our overall goal is to define the specific functions of marrow-resident macrophages in the regulation of red blood cell production. Currently, we are investigating the molecular mechanisms that enable EA-Macs to selectively engulf pyrenocytes at a tremendously high rate while maintaining appropriate support for developing erythroid cells. To address these questions, we are using automated high-dimensional flow cytometry analysis in combination with single cell transcriptomics in mouse models of erythropoiesis and anemia.