Cell death and immunity in cancer
We are interested in understanding the processes that regulate cell death, inflammation and immune homeostasis, and how this knowledge might be applied to deliver better anti-cancer drugs to the clinic.
Drugs that mobilise our immune system against cancer are dramatically improving care for many people, and research is rapidly moving ahead on the lab and the clinic.
It is now clear that dying cancer cells play an active role in the initiation of an anti-cancer immune response. However, a cell can die through different cell death pathways, and not every pathway can stimulate an anti-tumour immune response.
The emergence of a multitude of cell death mechanisms has shed new light on multiple molecular crosstalks between cell death pathways and innate immune pathways, and revealed new layers of complexity in the relationship between dying cells, adaptive responses and induced immunity.
Cell death pathways that are accompanied by the release of constitutive and inducible DMAPs (damage associated molecular patterns) are direct upstream drivers of an effective anti-tumour immune response.
For example, robust cross-priming requires receptor-interacting protein kinase 1 (RIPK1) to concomitantly induce both cell death and the production of DAMPs within dying cells. Decoupling RIPK1 signalling and necroptosis or inflammatory apoptosis reduces priming efficiency and tumour immunity.
Our programme focuses on studying proteins that reside at the crossroads of cell death and immunity (inflammation and adaptive responses), such as IAPs, RIPK1 or NLRP3, and orchestrate the assembly of multimeric scaffolds that control cell activation, apoptosis, necroptosis and pyroptosis, respectively.
This will help us to understand cell death and immunity in a new light, and allow us to manipulate current therapies so that they simulate a type of tumour cell death that is immunogenic, and in combination with immune checkpoint blockade, may lead to long-lasting anti-tumour immunity.
- The group’s finding has contributed to our understanding of how Inhibitor of APoptosis (IAP) proteins regulate cell survival and inflammation. They discovered that IAPs act as E3 Ub protein-ligases and Ub-receptors that regulate caspase-dependent as well as caspase-independent cell death.
- Further, their work exposed that IAPs control innate immune signalling by regulating activation of RIPK1, NFkB and MAPK signalling. The lab made several key contributions, which firmly established that IAPs function at the crossroad of cell death regulation and inflammation, a view-point that is currently being exploited in clinical trials with pharmacological inhibitors of IAPs.
- Recently, the group has identified IAPs as guardians of the ripoptosome, a large protein complex that can regulate apoptosis, necroptosis, cell motility and cytokine production. The discovery of the ripoptosome and its ability to kill apoptosis-resistant cancer cells has provided unexpected and exciting new insights into fundamental mechanisms through which cancer cells can be pushed into caspase-independent cell death. This has tremendous implication for the design of novel therapeutic approaches aimed at selectively destroying apoptosis-resistant cancer cells.
- The group also discovered novel regulatory mechanisms that help to explain how organisms mount a balanced immune response to effectively clear pathogens while avoiding deleterious immune activation and tissue damage.
- Further, they identified new and unexpected mechanism of regulation that will allow them to exploit the presence of cytokines of the tumour micro-environment to selectively kill tumour cells via immunogenic cell death. This observation will have major implications on the design of novel anti-cancer treatments that makes use of cancer-related inflammation, which is a driving force of tumour growth and treatment resistance. For the first time, it will be possible to rewire cytokine signalling to drive activation of cell death. This will not only improve tumour kill, but also help immunotherapy by improving cross priming of CD8+ T-cells.
- The group’s recent studies revealed Ubiquitin- and phosphorylation-dependent checkpoints that regulate tumour necrosis factor-induced cell death.
Our methods and techniques
Professor Meier and his team are using fly genetics, mouse models and patient derived organoids to investigate the complex relationship between cell death, immunity and tumorigenesis.
Since these pathways are conserved between flies and humans, their results are relevant for the better understanding of the mechanisms causing human diseases.
Particularly, we are investigating the role cell death and inflammation in adaptation to tissue stress, treatment resistance and tumour surveillance.
The lab is using the following methodologies:
Mass spectrometry, diGly Affinity Capture followed by mass spectrometric analysis, Cross priming Assays, Immunoprecipitation Assays, Cell Culture, Transfection, Infection, RNA Interference, CRISPR/Cas9-mediated genetic engineering, Time Lapse Imaging, Immunofluorescence, Confocal Microscopy, Proximity Ligation Assays, Cell Cycle-related techniques such as Cell Synchronization and Mitosis Timing, Isolation and Culture of Organoids, Cell Migration Assays, Dynamic BH3 profiling, Ubiquitylation Assays (in vitroand in vivo), TUBE purification, Deubiquitylation Assays, UbiCRest Analysis, Caspase Measurements, Cell Death Assays (FACS), Clonogenic Assays, 3D organoid culturing, Cloning, Real-Time RT-PCR, Yeast-two and three-Hybrid assays, Cell Competition assays, and other cell-based or molecular biology assays (see publications for details).