Targeting RIPK1 ubiquitylation to promote anti-tumour immunity
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Embargo End Date
ICR Authors
Authors
Jamal, K
Document Type
Thesis or Dissertation
Date
2019-11-30
Date Accepted
Abstract
Cancer heterogeneity is a key problem of current therapies leading to resistance. The way cancer cells die can lead to anti-cancer immunity, which is frequently referred to as "immunogenic" cell death. The aim of the project is to understand how TNF (Tumour Necrosis Factor), a master pro-inflammatory cytokine can cause "immunogenic" cell death. This death is dependent on activation of Receptor Interacting Protein Kinase 1 (RIPK1). Therefore, it is pivotal to understand how this kinase is regulated by a variety of checkpoints, which ensure that TNF stimulation induces NFkB signalling, inflammation and cell survival. However, the perturbation of these checkpoints induces TNF dependent cell death. Here, I have characterised the mechanism by which the E3 ubiquitin ligase Mind-Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. While depletion of MIB2 has little effect on NFkB activation, it sensitises cells to RIPK1- and caspase-8-dependent cell death. I find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating RIPK1 at specific lysines, thereby interfering with RIPK1's oligomerisation and RIPK1-FADD association. Together, my findings demonstrate that Mind Bomb 3 ubiquitin-ligases can function as additional checkpoints of TNF-induced cell death, selectively protecting cells from the cytotoxic effects of TNF. Furthermore, I have used a clinically relevant animal model to evaluate the therapeutic advantage of inducing RIPK1 dependent cell death. I have shown that Sma Mimetics (SM) (IAP degraders) augment the efficacy of the standard of care (SOC) treatment of extremity malignancies. Mechanistically, combination treatment with SOC/SM promotes RIPK1-mediated cell death, which significantly improves local disease control, increases infiltration/activation of CD8+ T cells and NK cells, and enhances the survival benefit of immune checkpoint blockade. My findings warrant a clinical trial to assess the survival benefit of RIPK1-induced immunogenic cell death in patients with advanced disease at limb extremities.
Citation
2019
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Cell Death and Immunity