Cell Death and Immunity Group

"Tumour Cell Death is not an endpoint, but the beginning of an immune response"

Our aim is to harness cell death and immunity to defeat cancer.

Cell death is integral to the immune response and acts as a beacon, a second messenger, that guides both immune system and tissue micro-environment to ensure tissue repair and homeostasis. Dying ca­­ncer cells are also crucial to anti-tumour immunity by stimulating the cross-priming of CD8+ T cells (Figure 1).

However, not all cell deaths are equal in stimulating an anti-tumour immunity. While some type of cell death forms are immunogenic, others are immunologically silent or even tolerogenic, shutting down T-cell responses. Therefore, understanding which type of cell death is immunogenic, and which therapies induce them, is of paramount importance for anti-cancer therapies to maximise CD8+ T cell activation.

In our laboratory, we study the effect of cell death pathways on anti-tumour immunity.

Figure 1. The cancer-immunity cycle (Chen et al., Immunity, 2013). Immunity in cancer is a cyclic self-propagating process. Each cycle starts with cell death and ends with a T cell response.

Our programme focuses on the crosstalk between cell death, inflammation and immunity in cancer. Immunogenic cell death is a successful dialog between a dying cell and a rightly disposed immune system.

If successful, this interaction promotes an immunogenic outcome proportional to the threat. Critical for the dialog are damage-associated molecular patterns (DAMPs), whose production varies depending on the type of cell death in quantity and quality.

How can we take advantage of the fundamental principles of immunogenicity (Figure 2)? Our improved understanding of the different types of cell death - apoptosis, necroptosis, pyroptosis, and ferroptosis - and their interconnectivity with innate and adaptive immunity has unearthed new opportunities to guide our immune system to fight cancer.

Our goal is to manipulate cell death signalling pathways so that they not only kill the cancer cell, but also guarantee an immunogenic outcome. This can be achieved using strategies that are based on ‘viral mimicry’. This simulates the presence of an imaginary pathogen, collaterally triggering an attack on the tumour and an immunisation against tumour antigens.

Additionally, since cancer treatment often fails because of the evolution of resistant clones, we aim to ‘steer’ cancer evolution by changing the fitness landscape of cancer cells while strengthening the one of surrounding healthy tissue.

The overarching goal of our research programme is to identify and understand the molecular mechanisms behind immunogenic cell death so they can be manipulated in cancer therapies. Our research themes are (Figure 3):

Theme 1: Immunogenic cell death in cancer

• Identify regulatory mechanisms of necroptosis/apoptosis/pyroptosis and DAMPs production in the tumour

• Study the therapeutic consequences of immunogenic cell death on tumour/immune interactions in breast and lung cancer

Theme 2: Winners versus Losers: Cell Competition in tumour evolution, heterogeneity and drug resistance

• Develop novel anti-cancer treatment approaches that target the competitiveness features of the tumour microenvironment to convert super-competitor cancer cells into super-losers.

figure 3: Research programme overview. Theme 1 (left): Immunogenic Cell Death (pushing current treatment regiments into immunogenic cell death). Theme 2 (right): Killing tumour cells by targeting the fitness landscape.

• We established that IAPs (Inhibitors of APoptosis proteins) 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. 
• We contributed to the characterisation of the ripoptosome, a large protein complex that can regulate cell death, mitosis, cell motility and cytokine production, with exciting implications for the design of novel therapeutic approaches aimed at selectively destroying apoptosis-resistant cancer cells. 
• We reported the first pre-clinical application of an in vivo treatment protocol for soft-tissue sarcoma that directly engages RIPK1-mediated immunogenic cell death.

Professor Meier and his group are using patient-derived organoids and animal models to investigate the complex relationship between cell death, immunity and tumorigenesis. Since these pathways are conserved between different species, it will be important to understand evolutionary principles that cause human diseases. Particularly, the laboratory is investigating the role of cell death, immunity and inflammation in adaptation to tissue stress, treatment resistance and tumour surveillance.