Research Group Signaling and Immunity

Specific T and B cell antigen receptors (TCR and BCR) expressed on the surface of lymphocytes recognize disease-causing pathogens that enter the human body. Antigen recognition of lymphocytes initiates an adaptive immune response, which efficiently eliminates the invading pathogens and builds up long-term immune memory to protect from reinfection. Cellular signaling cascades transmit the TCR and BCR signals inside T and B cells to orchestrate a physiological response leading to lymphocyte activation, differentiation and effector functions. We investigate the detailed molecular mechanisms of TCR and BCR signaling pathways in physiological settings. Our aims are to identify all critical players for immune signaling they are controlled. Thereby, we want to understand how lymphocyte signaling maintains the tight balance between optimal immune activation and immune tolerance, which can guide strategies for immune therapies in the future.

One focus of our work is the CBM signaling complex, a higher-order platform consisting of the core subunits CARD11, BCL10 and MALT1. The CBM complex acts as a gatekeeper and pacemaker for lymphocyte activation and it associates with a multitude of positive and negative regulators, leading to non-linear signal propagation. Due to its dual role as a scaffold component and a protease, MALT1 is of special interest for understanding the function of the CBM complex. The CBM complex serves as a paradigm how higher order molecular assemblies can facilitate activation or suppression of cellular response pathways by inducing proximity of large networks of proteins.

Survival and growth of many aggressive lymphoma rely on chronic B cell receptor (BCR) signaling. We have shown that constitutive activation of MALT1 protease contributes to the survival of the activated B cell-type of diffuse large B cell lymphomas (ABC DLBCL) a very frequent and highly malignant human hematologic malignancies. Thus, MALT1 is an attractive therapeutic target to treat hematologic malignancies. We are unraveling how aberrant signaling contributes to MALT1 protease activation in ABC DLBCL and other lymphomas. Further, we elucidate downstream mechanisms that link MALT1 to proliferation and survival of lymphoma cells. A special focus is how MALT1 elicits its function by acting on transcriptional and posttranscriptional gene networks in the tumor cells and in the tumor microenvironment. Further, we are searching for biomarker research to stratify patients that could profit from MALT1 targeting and to predict clinical responses.

Ubiquitin is a small protein that is attached covalently to many cellular substrate proteins to mark them for destruction or to modulate there function. More than 500 human proteins are involved in controlling ubiquitin conjugation and many of these proteins are involved in the regulation of cellular signaling pathways. We are investigating how the ubiquitin system impacts on immune and inflammatory signaling in physiological and pathological settings. With our work, we aim to propose new therapeutic targets to activate or suppressor immune responses and discover new candidate compounds that can modulate immune pathways in clinical settings. We also investigate how ubiquitin modifiers and substrates affect other cellular responses, as for instance cell activation by viral SARS-Cov2 factors or cellular trafficking pathways and the supply of cells with nutritients.

MALT1 acts as a tumor cell-intrinsic survival factor in malignant lymphomas and other solid cancer. In addition, MALT1 activation counteracts anti-tumor immunity by maintaining the activity of suppressive regulatory T cells in the tumor microenvironment. Thus, MALT1 protease is a promising target for cancer therapy. In an academic drug development program, we identified first-in-class inhibitor that specifically targets the immune protease MALT1. The favorable pharmacodynamic properties of the MALT1 lead inhibitor allow selective targeting of MALT1 in the tumor microenvironment (TME), thereby eliciting an increased anti-tumor immunity in solid cancer. This highly innovative clinical concept is currently tested in an early clinical trial (NCT04859777). Current research is optimizing MALT1 inhibitor compounds and addressing the mode of action of MALT1 inhibitors in different cell types and tissues.