Tumor Heterogeneity Metastasis and Resistance

Translational Immunology

Translational Hepatology

We seek to decipher the pathophysiology of immune paresis and monocyte and macrophage dysfunction in patients with cirrhosis of the liver. A detailed understanding of the mechanisms is desired in order to understand their infection susceptibility, identify prognostic markers and define potential future immunotherapeutic targets that may enhance innate immune responses and reduce the need for liver transplantation and death.

Helminth Immunology

The Helminth Immunology group conducts basic and preclinical research aiming to enhance our understanding of host pathogen interactions with the long-term goal to identify new strategies of intervention against hookworms. We study helminth parasites, because they are fascinating and complex organisms that have co-evolved with us for so long that they have marked deeply our immune system. We use a multidisciplinary approach combining traditional parasitology, molecular parasitology and immunology to uncover the cellular and molecular events involved in parasite evasion of host immune attack, as well as weaknesses in parasite development that can be targeted with drugs.

Translational Diabetes

Our research focusses on the role of macrophage polarization in metabolic disease such as type 2 diabetes and obesity. Polarization of macrophages is characterized by their inflammatory activation and metabolism status. Gaining knowledge about the polarization of macrophages is crucial for a better understanding of the pathogenesis of metabolic disease. Deliberate modulation of macrophage polarization could help to improve glycemic control. Further, we are interested in the role of gut mucosal immunity in mediating metabolic disease. Thereby, we are studying how different environmental factors such as high-fat diet intake alter intestinal macrophages and what the down-stream effects are in terms of metabolic disease. The overall aim of our research is to better understand how innate immunity contributes to metabolic disease, especially intestinal macrophages, and how they could be targeted for future immunometabolic therapies in metabolic disease.

Experimental Immunology

The Experimental Immunology group studies the role of non-peptide-specific T cells in the human immune response and their participation in diseases. Novel approaches to investigate human T cell function, TCR repertoire and cloning are developed to investigate these cells in human tissues.

Clinical Neuroimmunology

Molecular and immunological analysis of Multiple Sclerosis
Our research focuses on the molecular and immunological analysis of multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system (CNS) disease, and number one cause of neurological disability in young adulthood. We pursue two main research lines: 1) Relevance of B-cells and antibodies in MS pathogenesis. 2) Exploration and validation of biomarkers in cerebrospinal fluid and blood as tools for therapeutic decision making for persons with MS. Both approaches provide novel tools for monitoring the efficacy of current and emerging therapies of MS.

B cells and their targets in MS
B-cells have a major role in the pathogenesis of MS. Depletion of B-cells leads to a remarkable amelioration of the disease. The mechanisms by which B-cells impact MS are however incompletely understood. Our research focuses on the identification of novel B-cell autoantigens and the characterization of the interaction of auto-aggressive B-cells with the CNS. We could show that antibodies against native myelin oligodendrocyte glycoprotein (MOG) identify a subset of patients with neuromyelitis optica and are also found in SLE patients with CNS involvement (Pröbstel et al., 2015; Pröbstel et al., 2019). Using transgenic animal models, we were able to prove a new concept how infection could lead to the development of autoantibodies like those against MOG. We identified the co-capture of membrane antigens by the B cell receptor as a key step in initiating an autoimmune response in the context of an infection (Sanderson et al., 2017). This work is now continued by analyzing the capacity of B cell to migrate to peripheral tissues including the CNS and harvest their cognate and non-cognate antigens from the tissue. The phenomenon of membrane capture can also be used to purify B cells of a certain specificity from blood (Zimmermann et al., 2019) and to identify novel B cell autoantigens in MS.

Cancer Neuroscience

Accumulating evidence indicates that cancer and the nervous system bear a much closer, entangled relationship than had been previously appreciated. The innervation landscape of the tumour microenvironment appears to impact tumour progression, but the mechanisms underlying this observation remains completely unresolved and understudied. The aim of our research is to use powerful complementary technologies to address a key interdisciplinary question in cancer – The role of neuro-immune interactions in tumour progression and anti-tumour immunity.

Diabetes Research

Liver Immunology

A specialized T cell subset belonging to the family of innate-like lymphocytes is highly abundant both in the gut mucosa and the liver. These mucosal-associated invariant T (MAIT) cells respond to bacterial metabolites produced in the vitamin B2 (riboflavin) synthesis pathway. Our aim is to elucidate the role of MAIT cells in selected liver diseases, including autoimmune liver diseases, steatohepatitis and viral hepatitis, and in the fibrogenic response in the liver. Due to their location and high abundance in the liver, and their responsiveness to bacterial products and various cytokines, we hypothesize that liver-resident MAIT cells play a role in the pathogenesis of liver diseases and that changes in MAIT abundance, activation status, and cytokine expression profile influence disease development and outcome.

Developmental Immunology

New subsets of functionally distinct innate lymphoid cells (ILCs) have been identified in recent years, which are essential for the development and homeostasis of lymphoid tissues, and have important roles in determining the outcome of infections and inflammation. The major objective of the Developmental Immunology research group is to identify the molecular events underlying the growth and function of ILCs and lymphoid organs for the innate and adaptive immune system. In particular, we focus on the mechanisms of ILC differentiation, the role for tissue-specific transcriptional regulation of ILC compartments and the key pathways that regulate ILC immune functions under steady-state and proinflammatory conditions. Finally, we seek to identify ILC subsets, which are protective in chronic inflammation (e.g. colitis) and tumor diseases.

Allergy and Immunity

Hepatology

The Hepatology research group is interested in the innate immune response to viral hepatitis and in the pathogenesis of hepatocellular carcinoma.

Immunobiology

Our research is focused on the translational aspects of lymphocyte function and its metabolic basis. The goal of our work is to understand the driving mechanisms in patients suffering from disorders of immunometabolic regulation.

Transplantation and Clinical Virology

Our experimental virology studies focus on BKPyV in primary human renal tubular epithelial cells as key target of BKPyV nephropathy in kidney transplants. For the first time, we identified an evolutionarily conserved functional role of viral agnoprotein, which promotes innate immune evasion by disrupting the mitochondrial membrane potential, fragmenting the mitochondrial network, and targeting the damage mitochondria for autophagy. Regarding adaptive immunity, we identified more than 70 immunodominant 9mer epitopes recognized by BPyV-specific CD8 T-cells controlling BKPyV-DNAemia. Notably, we developed a novel peptide expansion protocol of BPyV-specific CD8 T-cells in vitro en route to a safe peptide-based protection by adoptive T-cell transfer and vaccination. We also identified variant amino acid exchanges in the conserved BKPyV-early protein, which mediate escape from CD8 T-cell control.
We plan to reconstitute 3-dimensional renal tubule kidney culture and organoid models for BKPyV infection and antiviral T-cell control as an animal-free surrogate for pre-clinical models of viral immune control and to design phase I clinical vaccination studies in healthy volunteers.

Pediatric Immunology

The thymus constitutes the primary lymphoid organ for the development and selection of T lymphocytes, a cell type critical for the function of the adaptive immune system. The thymus is composed of different cell types and only their correct differentiation and architectural organisation ensure a normal function.  Several genetic disorders and acquired pathologies have been identified that effect not only the regular development, but also the function of the thymus. To study the physiology of thymic development and to further characterise the pathologies that evolve as a consequence of damage to the thymus the laboratory has developed mouse models to study apparent thymic development and function. The Holländer laboratory is jointly run with facilities and resources  at the Weatherall Institute of Molecular Medicine, University of Oxford.

Brain Tumor Immunotherapy

Molecular Immune Regulation

Our group is interested in understanding molecular mechanisms underlying immune regulation. We are particularly interested in deciphering the role of microRNAs in T cells. We have previously demonstrated the importance microRNAs for regulatory T cells (Treg) and T follicular helper (TFH) cells. Based on these findings we aim to deepen our understanding of molecular networks regulated by individual miRNAs. We employ various genetic models and recently developed a gene editing protocol for efficient gene engineering in primary T cells. These new tools opened doors to use genetic engineering to develop new therapeutic concepts for a variety of diseases.

Infection Biology

Infectious diseases remain a leading cause of death worldwide. Over the last decades huge advances have been achieved in medicine including complex surgeries, cancer treatment and transplantation. Yet, the success of modern medical procedures is endangered by infectious complications. No or very few new anti-microbial drug substances have been discovered over the last 30 years, which means that very limited therapeutic options are available especially in the context of difficult-to-treat or multi-drug resistant infections. Our research group explores host-specific aspects of infectious diseases in a strong translational setting and investigates new treatment strategies with the overarching goal to improve outcome of infections.

Host interaction and new targets for treating bacterial infections  Invasive staphylococcal infections are often resilient to antibiotic treatment despite in vitro activity of the applied antibiotics. This has been attributed to the vast amount of pathogen but also host-related factors. Our goal is to unravel mechanisms of the pathogen and host evasion in the context of treatment failure and to find new strategies to treat these patients.

Virus-specific T-cell therapies for the clinics   Viral infections contribute to substantial morbidity in immune compromised patients particularly after transplantation. Anti-infective drugs alone are often ineffective due to the lacking immune responses or are associated with a substantial toxicity and development of resistant variants. Adoptive transfer of pathogen-specific donor-derived T cells can restore the lacking recipients’ T-cell function. We have pioneered virus-specific T-cell therapies in Switzerland. Our goal is to optimize the T-cell product and its T-cell composition for improved and long-lasting virus control.  

Immune Cell Biology

Our lab investigates the cellular and molecular processes leading to CD4 T cell fate diversification during infection. We are examining single cell dynamics of T cell fate acquisition in vitro as well as the transcriptional basis underlying individual T cell fates in vivo.

Molecular Virology

Our research strategy focuses on the changing viral properties of HIV-1 over the course of infection during suppressive therapy. We recently demonstrated that envelope properties of HIV strongly correlate with immune-recovery and disease outcome. In particular, the X4-tropism of virus but also in silently infected cells, correlating with poorer outcomes in therapy-naïve individuals, appears to trigger superior HIV control during effective treatment. We thus aim at characterizing HIV inside the key T-cell populations in early periods of therapy to identify cell populations driving selective virus elimination and understand the preservation/re- establishment of crucial immune compartments.

Experimental Rheumatology

In the experimental rheumatology laboratory we are interested in the immunopathogenetic mechanisms of inflammatory rheumatic diseases with special focus on mechanisms of the innate immunity. Our research topics include the regulation of inflammatory pathways during macrophage differentiation and polarization. Immune-modulation by extracellular vesicles and the identification of their functional load in rheumatoid arthritis, particularly microRNA. The role of neutrophil extracellular traps and cell-free mitochondrial DNA in the pathogenesis of various rheumatic diseases. We follow a translational approach, using patient materials such as blood and synovial fluid and in vitro cell cultures with primary cells.

Cancer Immunotherapy

Improving cancer immunotherapy Our main goal is to improve immunotherapy for cancer patients by using translational in vitro and in vivo tumor models, performing correlative analysis of patients treated with immunotherapy and conducting early clinical interventional trials (also see link to Medical Oncology).  One of our research focus is on the role of glycans and glycan-binding receptors in anti-cancer immunity. Glycans can mediate important interactions with immune cells and manipulation of glycans and glycan-binding receptors (lectins) bear a great potential to improve anti-tumor immune reactions. Glycan-mediated interactions in cancer immunology are significantly underexplored and could be used to improve anti-cancer immunity. Our group has studied the interaction between glycans that contain sialic acids (siaologlycans) and their interaction with Siglec receptors on immune cells and have demonstrated that this pathway can be targeted to augment T cell stimulation and tumor control. Current goals include improvement of cancer immunotherapy by modifying glycans in the tumor microenvironment and glycans of cellular products for adoptive cell therapies including genetically modified T cells.  An additional focus of our group is the improvement of immune checkpoint blockade and adoptive cellular therapies by investigating mechanisms and patterns of resistance to these therapies. To this end, we are investigating the tumor microenvironment as well as circulating immune cells in patients undergoing immune checkpoint blockade or adoptive T cell transfer. Identified pathways are further studied in the laboratory for their potential as new targets to improve antitumor immune responses.

Translational Neuroimmunotherapy

Cell-migration is fundamental to protective immunity but also plays a central role in the pathogenesis of autoimmunity. Our general aim is to assess migration of primary human T cells within specific subpopulations on a single cell level in multiple sclerosis (MS). Most of our insight into T cell migration is based on monitoring of bulk cell populations in classical in vitro migration assays. However, clinical samples containing only small numbers of cells are not amenable for such assays. We have developed microfluidic devices to study the migration characteristics of primary human T cells. Characterizing migration properties of individual human T cells ex vivo, we have already established the proof of concept that this technique can overcome limitations of standard migration assays. With the help of microfluidics we aim at assessing migration characteristics of immune cells derived from the cerebrospinal fluid of patients with MS and relate these findings with clinical phenotypes.

Experimental Immunology

My research interests are centered on antigen-specific recognition by T lymphocytes and in particular on the role of T cells recognizing lipids and metabolites during autoimmune diseases, infection and cancer. The lack of antigen structural changes during immune selection and the absence of functional polymorphism in CD1 and MR1 antigen-presenting molecules, make T cell therapy based on the recognition of non-peptidic antigens, very powerful. Present goals are the identification of T cell signatures as relevant disease-specific biomarkers and exploitation of CD1 and MR1-restricted T cells in novel immunotherapeutic strategies.

Skin Biology

Gastroenterology

Inflammatory bowel diseases (IBD), such as Crohn`s disease and ulcerative colitis, are chronic relapsing diseases with increasing incidence in the developed world. Innate and adaptive immune responses to constituents of the intestinal microbiota are essential for the development of IBD. Intestinal mononuclear phagocytes are in direct contact with the intestinal microbiota, initiate innate immune responses and shape adaptive immune responses. To reduce the complex interactions between phagocytes and T cells in presence of the intestinal microflora with vast array pf potential antigens, an antigen-specific colitis model was developed. In this model intestinal phagocytes sample luminal antigens and transfer these antigens to dendritic cells, which migrate to the mesenteric lymph nodes to prime prime T cells. Mononuclear phagocytes in the gastro-intestinal tract are of importance for the sampling of constituents of the microbiota, the initiation of innate and adaptive immune responses.

The Pieters Laboratory | Biozentrum Website

Immune Cell Population Size Control

Our research aims to understand the mechanisms via which immune cells sense and maintain the size of multicellular populations at their appropriate density. In particular, we investigate the role of coronin signaling to achieve proper cell population size control. Knowledge on how immune cell population sizes are being controlled may be important for a better understanding of the body’s immune defense mechanisms as well as the processes that underlie immune cell homeostasis and activation by ‘self’ triggers such as occur during autoimmunity.

Experimental Virology

The Experimental Virology lab is interested in virus – host interactions in the broadest sense with a special emphasis on adaptive immune responses. Specifically, we study antiviral B cell and antibody responses, antiviral T cell immunity and the role of virally triggered alarmins (e.g. interleukin-33) in this context, viral pathogenesis and immune evasion as well as virally delivered vaccines and immunotherapy.

Experimental Neuroimmunology

The Experimental Neuroimmunology research group aims at understanding the functional diversity and antigen specificity of B cells and their interaction with gut microbiota that are underlying immune-mediated diseases with a focus on the central nervous system. We strive to develop strategies to deplete pathogenic B cells and foster immune regulatory responses through targeted manipulation of the gut microbiome that can be translated back to the clinic to treat patients with multiple sclerosis and related diseases.

Immunodeficiency

My lab is interested in primary (genetically determined) immunodeficiencies/immune-dysregulations (PID) in humans. PID may present with susceptibility to infections or autoimmunity. Up to date, more than 300 PID entities have been described and the number is rapidly increasing. Patients with diagnosed PID (at the PID clinic of the Basel University Hospital headed by Prof. Mike Recher) are enrolled into a prospective cohort that analyzes the exact clinical presentation and links it with extensive immune phenotyping, functional experiments (including immune-metabolic profiling) and next generation sequencing. We aim to identify disease-causing mutations, describe novel PID entities, and to develop novel diagnostic approaches. This may facilitate personalized immunotherapy of these patients. In a complementary, more basic immunology approach, the fundamental link between susceptibility to infection and autoimmunity seen in PID patients is studied in murine models of graded RAG deficiency.

Laboratory for Systems and Synthetic Immunology, ETH Basel

Viral Immunology

The Viral Immunology group studies human immune responses to viral infection and vaccination using a combination of functional antibody and B cell receptor repertoire analyses. The goal of our research is to characterize immune responses in African compared to U.S. and European populations, with a current focus on responses to SARS-CoV-2 and other human coronaviruses as well as to COVID-19 vaccination. We also develop viral antigen capture assays based on human and mouse monoclonal antibodies that we generate by antigen-specific single B cell sorting and hybridoma technology. Assays will be used to study the epidemiology of viral infections in African populations.

Jürg Steiger

Transplantation Immunology & Nephrology

Transplantation immunology, immunological risk assessement, epidemiology in transplantatioon, cohort studies.

Clinical Immunology

Our group is interested in understanding pathogenic mechanisms leading to systemic autoimmunity (such as occurring in systemic lupus erythematosus), in particular the role of the complement system and autoantibodies against complement components. In addition, we are studying the role of functional complement deficiency in different settings. Our studies are trying to connect clinical questions with basic research.

Cancer and Immunobiology

Our research covers molecular functions of phosphoinositide 3-kinase (PI3K) in chronic inflammation, allergy and cancer. We have established PI3K as a relay downstream of G protein-coupled receptors (GPCRs), which is crucial for immune cell migration and adhesion. Moreover, activation and degranulation of mast cells by antigen/IgE depends on PI3K, a process that involves also a non-dogmatic activation of PI3K by a Ca2+/protein kinase C-dependent mechanism. Interestingly, PI3K also controls thermogenesis and obesity-induced inflammation, and controls cardiovascular events such as atherosclerosis and cardiac contractile responses. Collaborations with industry lead to the development of PI3K-specific, bioavailable inhibitors; and novel tools to manipulate and measure cellular PIP3 established a role for compartmentalized PIP3 signaling. Collaborative efforts with PIQUR Therapeutics AG Basel, generated PQR309, which is now in phase II clinical trials.

Cancer Immunology