Title: Damage-associated Molecular Patterns: revealing the molecular communication between dying cancer cells and the immune system
Other Titles: Damage-Associated Molecular Patterns: onthullen van de moleculaire communicatie tussen stervende kankercellen en het immuunsysteem
Authors: Garg, Abhishek Dinkarnath
Issue Date: 25-Sep-2012
Abstract: Cell surface-exposed calreticulin (ecto-CRT) and secreted ATP are crucial damage-associated molecular patterns (DAMPs) for immunogenic apoptosis. Here, immunogenic apoptosis is a type of cancer cell death subroutine which is apoptotic in nature but accompanied by ‘enhanced immunogenicity’ as opposed to immunosuppression or tolerogenicity which accompanies the normal physiological apoptosis. DAMPs, which play an important role in mediating this enhanced immunogenicity, are molecules that are normally hidden within live cells (where they perform pre-dominantly non-immunological functions) however they tend to acquire immunomodulatory functions once secreted/surface exposed by dying/stressed/damaged cells. Previously described inducers of immunogenic apoptosis (certain chemotherapeutics) relied on an endoplasmic reticulum (ER)-based (reactive oxygen species (ROS)-regulated) pathway for DAMP exposure/secretion. However, these inducers caused immunogenic apoptosis through an ‘off target’ effect thereby making the resultant immunogenicity secondary in character and prone to tumour/cancer microevolution-based resistance.During my PhD research, we found that after hypericin-based photodynamic therapy (Hyp-PDT), which generates ‘on target’ ROS-mediated ER stress, dying cancer cells undergo bona fide immunogenic apoptosis characterized by phenotypic maturation and functional stimulation of (human) dendritic cells (DCs) as well as induction of a protective anti-tumour immune response, in vivo. Intriguingly, early after Hyp-PDT the cancer cells displayed ecto-CRT and secreted ATP through overlapping PERK-orchestrated pathways that required a functional secretory pathway and phosphoinositide 3-kinase (PI3K) p110alfa-mediated plasma membrane/extracellular trafficking. Interestingly, eIF2alfa phosphorylation and caspase-8 signalling which were important for chemotherapeutics-induced ecto-CRT were dispensable for Hyp-PDT induced ecto-CRT. Moreover, we found that Hyp-PDT induced ecto-CRT (in contrast to chemotherapy-induced ecto-CRT) was ERp57-independent. We also identified LRP1 as the surface docking site for ecto-CRT and found that depletion of PERK, PI3K p110alfa and LRP1 but not caspase-8 reduced the immunogenicity of the cancer cells. These results unravelled a novel PERK-dependent subroutine for the early and simultaneous emission of two critical DAMPs during Hyp-PDT induced ‘on target’ immunogenic apoptosis. Thus, research done during my PhD has shown that there is a great need to increase the awareness (amongst patients and oncologists) that it is possible for the immunogenicity of a dying cancer/tumour cell to be accentuated to cause instigation of potent anti-tumour immunity if a proper therapy like Hyp-PDT is used; a message that has important socio-economic relevance. In terms of a practical implementation, the research done during my PhD can help in efficient Hyp-PDT based production of autologous anti-cancer DC vaccines against cancers like glioblastoma and melanoma. Moreover, for the preparation of autologous anti-cancer DC vaccines, Hyp-PDT has a higher probability of overcoming various immunogenicity resistance mechanisms (e.g. caspase-8 ablation based) employed by tumours than currently characterized chemotherapeutic inducers of immunogenicity. Hence, Hyp-PDT induced immunogenicity (if implemented clinically) promises to have better health economic implications.
ISBN: 9789461650610
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Cell Death Research & Therapy

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