Abstract
The new concept of Immunogenic Cell Death (ICD), associated with Damage Associated Molecular Patterns (DAMPs) exposure and/or release, is recently becoming very appealing in cancer treatment. In this context, PhotoDynamic Therapy (PDT) can give rise to ICD and to immune response upon dead cells removal. The list of PhotoSensitizers (PSs) able to induce ICD is still short and includes Photofrin, Hypericin, Foscan and 5-ALA. The goal of the present work was to investigate if Rose Bengal Acetate (RBAc), a powerful PS able to trigger apoptosis and autophagy, enables photosensitized HeLa cells to expose and/or release pivotal DAMPs, i.e. ATP, HSP70, HSP90, HMGB1, and calreticulin (CRT), that characterize ICD. We found that apoptotic HeLa cells after RBAc-PDT exposed and released, early after the treatment, high amount of ATP, HSP70, HSP90 and CRT; the latter was distributed on the cell surface as uneven patches and co-exposed with ERp57. Conversely, autophagic HeLa cells after RBAc-PDT exposed and released HSP70, HSP90 but not CRT and ATP. Exposure and release of HSP70 and HSP90 were always higher on apoptotic than on autophagic cells. HMGB1 was released concomitantly to secondary necrosis (24 h after RBAc-PDT). Phagocytosis assay suggests that CRT is involved in removal of RBAc-PDT generated apoptotic HeLa cells. Altogether, our data suggest that RBAc has all the prerequisites (i.e. exposure and/or release of ATP, CRT, HSP70 and HSP90), that must be verified in future vaccination experiments, to be considered a good PS candidate to ignite ICD. We also showed tha CRT is involved in the clearance of RBAc photokilled HeLa cells. Interestingly, RBAc-PDT is the first cancer PDT protocol able to induce the translocation of HSP90 and plasma membrane co-exposure of CRT with ERp57.
Highlights
The concept of tolerogenic apoptosis [1] has been integrated with that of immunogenic apoptosis or Immunogenic Cell Death (ICD) [2]
Rose Bengal Acetate (RBAc)-PhotoDynamic Therapy (PDT)-induced death in HeLa cells To determine the RBAc-PDT-induced death in HeLa cells, they were recovered for different periods after the PDT
We recently reported the efficient induction of ROS-mediated apoptosis and autophagy in HeLa cells upon RBAc-PDT [31]
Summary
The concept of tolerogenic apoptosis [1] has been integrated with that of immunogenic apoptosis or Immunogenic Cell Death (ICD) [2]. DAMPs, normally hidden within live cells, perform predominantly non-immunological functions and acquire immunomodulatory activities once secreted or surface exposed on dying or stressed/damaged cells [5]. DAMPs involved in the ICD are: surface exposed calreticulin (ecto-CRT) [6,7], Heat Shock Protein 70 (ecto-HSP70) and 90 (ecto-HSP90) [8,9,10]; secreted ATP [11,12]; passively released High Mobility Group Box 1 (HMGB1) and HPSs or chaperokines [11,13], DNA [14], uric acid [15], S100 protein [16], sphingosin [17] and they can be categorized on the basis of the death process stage during their occurrence, the relocation place, the release mechanism, the origin and the mechanisms of action [18,19]
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