Research
Health vs disease: how do environmental factors shape immune development and risk of immune mediated diseases?
A major research goal of the laboratory is to decode the environmental cues that shape the development and functional maturation of the post-natal immune system and determine how dysregulation can lead to immune-mediated diseases.
Using state of the art single cell ‘omics’, advanced imaging techniques and sophisticated genetically engineered mouse models, our work aims to decode cellular circuitry between immune and non-immune cells.
Through the study of unique clinical cohorts at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, our work transitions between laboratory experimental research and human disease focused research.
Early life immune tolerance
How is immune tolerance established in early life and maintained in adulthood?
Dramatic changes in the microbiota and diet during early life pose a challenge to the developing immune system. We are exploring the mechanisms by which the immune system establishes and maintains tolerance to these environmental antigens.
Work from the lab identified a previously uncharacterized antigen-presenting cell lineage, named Thetis cells, and demonstrated their role in instructing peripheral regulatory T cell development and tolerance to both gut microbiota and food antigens during early life. Our studies revealed transcriptional homology between Thetis cells and medullary thymic epithelial cells, highlighting parallels between mechanisms of thymic and peripheral tolerance. These discoveries raise key questions which our work seeks to address:
What regulates the developmental wave of Thetis cells in early life?
How do Thetis cells discriminate between harmless commensal microbes and pathogens?
What are the mechanisms by which Thetis cells instruct immune tolerance?
Do Thetis cells regulate tolerance to self antigens?
Do perturbations in Thetis cell development and function lead to autoimmune and inflammatory disease?
Immunity and Inflammation
Dendritic cells in inflammation
How do dendritic cells initiate diverse inflammatory responses tailored to the nature of the pathogen? We have uncovered two dendritic cell subsets, cDC2A and cDC2B. Using a combination of advanced spatial imaging techniques, single cell profiling and computational approaches to decode the cellular circuitry between dendritic cells, immune and stromal cells, our work addresses the following questions:
What are the molecular programs underlying dendritic cell heterogeneity?
What are the signals that shape the balance between dendritic cell subsets within the tissue?
How do distinct dendritic cell microenvironments influence T cell mediated immunity?
What is the role of cDC2 subsets in CD4 T helper cell responses?
We have established novel genetic models to temporally perturb dendritic cell lineages and our research addresses their role in inflammation, tumor immunity and tolerance.
Tumor progression, metastasis and cancer immunotherapy
How does the tumor microenvironment influence dendritic cell differentiation and in turn how to intra-tumoral dendritic cells influence tumor growth and metastasis?
Dendritic cells are imprinted by the tissue in which they reside. Through our studies of tissue specific dendritic cell heterogeneity we aim to understand:
How does the site of the tumor, with its distinct repertoire of tissue associated immune cells, shape the tumor immune response?
What are the mechanisms by which distinct dendritic cell subsets regulate tumor growth and metastasis?
As the gatekeepers to T cell mediated immunity, dendritic cells harbor enormous therapeutic potential for cancer immunotherapy. By decoding the distinct functional roles of dendritic cell subsets, our aim is to translate single cell immunology into novel therapeutic approaches for enhanced tumor immunity.
Lack of data on the immune landscape of both healthy pediatric tissues and pediatric solid tumors limits rational use of cancer immunotherapy in children. The Brown Lab is committed to mapping the developing human immune system and its interaction with solid tumors in order to develop novel immunotherapeutic targets in pediatric cancer.