EPIMAC:
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 involves human 3D skin-culture models to mimic the in vivo environment of LC cells isolated from skin.
In parallel, we have developed a unique profiling setup to identify and functionally characterize the interplay of several important signaling pathways, regulating the expression of immune checkpoint molecules in macrophages.
MACPATH:
The goal is to characterize the epigenetic determinants of macrophage function, in order to boost their activity towards killing pathogens. We utilize our CROP-seq technology to systematically assess the epigenetic requirements of macrophage function in response to infection. Macrophages are exposed to an array of pathogen associated molecular patterns 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 is in parallel applied to identify the epigenetic basis of trained innate immunity in an in-vitro model of long-term interferon exposure. The successful project will result in the identification of targets for small molecules or genomic/epigenomic engineering to induce sustained training of in-vitroengineered CAR-macrophages.
INTERCOM:
Cell-cell communication (CCC) is a fundamental process and broadly relevant to human health and disease. Alterations of this communication in the tumor ecosystem (TES) contribute to tumor development. Recent progress in understanding CCC in the TES has identified macrophages as key players in orchestrating tumor immune responses. Despite recent progress in the development of checkpoint inhibitors to (re-)engage immune cells in tumor-targeting processes, many tumor types, including micro-satellite stable colorectal cancer (MSS- CRC) remain resistant to checkpoint therapy.
The project addresses the exciting perspective of a TES-wide characterization of CCC and to interfere with the tumor cell – macrophage communication axis, which we hypothesize contributes to a suppressive TES. The project is focused on the identification and functionality testing of CCC in the CRC TES, given (i) the high frequency of immuno-suppressive acting macrophages in MSS-CRC and (ii) comprehensive access to both fresh and fresh-frozen patient material and established patient-derived organoid and tumor slice culture workflows for testing our hypothesis. We will identify critical mediators of cytokine signals in macrophages, using a functional perturbation assay. A chemical biology screen with scRNA-seq as a read-out will identify and connect proteins and small molecules that can interfere with communication. Removal of cell types from the TES by CAR-T cells in tumor slice cultures and introduction of re-programmed, shielded macrophages will functionally test their ability to re-arrange the CRC TES.
INTERCOM will generate deep insights into the relationships between tumor-associated macrophages and other cells of the CRC TES. Identification of molecules involved in communication to macrophages will pioneer a new avenue for therapeutic interventions by providing small molecule inhibitors and/or genetic targets to shield macrophages and to maintain an anti-tumoral state.
SMALL CELL COLLIDER:
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.
MACRARE:
Our prime access to clinical material and the close collaborations with clinicians at the department, allows us to address clinically important questions in rare skin diseases. 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.
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.