‘autophagic’ cell death has only been recently shown to be capable of releasing HMGB1 yet it remains to be clarified whether ‘transiently’ activated autophagy could actually assist in or hinder the exposure of certain DAMPs. Here, since PDT is capable of activating both these cell death pathways depending upon the dose or 19
post-PDT recovery time, it could be assumed that PDT-based modalities could probably help us solve the question of overlap between DAMPs exposed/released by apoptosis and/or autophagy. And last but not the least is the relatively unexplored area of correlation between a particular spectrum of DAMPs and stress on a particular sub-cellular organelle. For a long time, a lot of different DAMPs exposed or released by cells under stressed or dying conditions were being analyzed but in cases of active exposure/release, the mechanisms governing the translocation or secretion were elusive. It was only in last few years that more in-depth knowledge of DAMP translocation and secretion pathways was unearthed thereby giving some idea about correlation between stress targets within the cells and particular DAMPs. For instance, in case of ecto-CRT (anthracyclines, oxaliplatin and ionizing radiations) and ecto-HSP90 (bortezomib), it was shown that agents inducing ER-stress (directly or indirectly) could instigate or assist in their exposure (75, 106), thereby making ER an important sub-cellular organelle for DAMPs. However the same is not applicable to DAMPs like HMGB1 and HSPs e.g. while in most cases the exact pool from which surface HSPs originate is not known, yet Photofrin-PDT which primarily exerts stress on Golgi apparatus and plasma membrane has been shown to cause ecto-HSP70 exposure (90, 92). Thus, even though ER has been shown to be potential pool for certain DAMPs yet the conundrum of correlation between particular DAMPs and stress on a particular sub-cellular organelle still exists. We envisage that PDT is one of those modalities that could help us efficiently solve this outstanding question. There is a well characterized panel of photosensitisers available, which tend to localize in various different or a particular organelle; thus, usage of PDT-based stress on these organelle and subsequent analysis of exposed/secreted DAMPs could probably help us in revealing the sub-cellular pool from which a particular DAMP originates. PDT and its effects on immune system Direct effects of PDT on immune cells: capable of resetting immunosuppressive tumour microenvironment? PDT is frequently considered to be a selective antitumor therapeutic procedure. While indeed most of the photosensitisers seem to better accumulate in tumour as compared with normal cells the damage is usually conferred to all types of cells within the illuminated area. Therefore, selectivity of PDT mainly results from the fact that illumination itself limits the area that is being damaged and includes tumour cells, tumour stroma (including vasculature and fibroblasts) and tumour infiltrating cells of the immune system. Numerous
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