The goal of EpiMac is to identify epigenetic key players for macrophage differentiation in health and disease. We will utilize our recently developed CROP-seq technology for a systems immunology approach towards identifying the epigenetic requirements for macrophage development in-vitro, starting at the level of mouse hematopoietic stem cells (HSC) with a focus on Langerhans cell (LC) development. Based on those results we will screen for epigenetic modifiers required to generate a cancer cell from a developing macrophage. This will involve human 3D skin-culture models to mimic the in-vivo environment of LC cells isolated from skin. In parallel we will screen for the epigenetic requirements of tissue resident macrophage development in-vivo

The goal is to characterize the epigenetic determinants of macrophage function to boost their activity towards killing pathogens. We will utilize our CROP-seq technology to systematically assess the epigenetic requirements of macrophage function in response to infection. Macrophages will be exposed to an array of pathogen associated molecular patterns in order to identify similarities and differences in the requirement of epigenetic modifiers and key-pathway components in the response to pathogen derived stimuli, interferons and inflammation-promoting cytokines. The screening strategy will in parallel be applied to identify the epigenetic basis of trained innate immunity in an in-vitro LPS and beta-glycan model. The successful project will result in the identification of targets for small molecules or genomic/epigenomic engineering to induce sustained training of in-vitro engineered CAR-macrophages. 

We are studying the effect of cellular interactions at the single cell level using a novel platform for analyzing cell-cell interactions. The platform provides a maximally controlled environment to foster cell interactions followed by their separation and subsequent single cell RNA-sequencing. The resulting transcriptome profiles can be analyzed to study novel pathway interdependencies and effects of immune cell priming and training.

We use high throughput single-cell RNA-seq and epigenome profiling as well as cell based in-vitro assays to characterize the initiating cell in granulomas. Furthermore, we will identify the processes leading to the formation of giant cells, multi-nucleated cells resulting from fusions of macrophages, which can be regularly found in granulomatous diseases.

Cutaneous T cell Lymphoma (CTCL) is a rare disease with no existing curable treatment and no selective biomarkers for patient stratification. Unbiased profiling of CTCL biopsies in early and late stages of the disease revealed a subset of tumor infiltrating macrophages that undergo progressive changes along with the disease. We will phenotypically characterize the tumor immune microenvironment of CTCL and identify potential targets for treatment as well as cellular and molecular biomarkers for improved patient stratification.