Many faces of DAMPs in cancer therapy

A new concept of immunogenic cell death (ICD) has recently been proposed. The immunogenic characteristics of this cell death mode are mediated mainly by molecules called ‘damage-associated molecular patterns’ (DAMPs), most of which are recognized by pattern recognition receptors. Some DAMPs are actively emitted by cells undergoing ICD (e.g. calreticulin (CRT) and adenosine triphosphate (ATP)), whereas others are emitted passively (e.g. high-mobility group box 1 protein (HMGB1)). Recent studies have demonstrated that these DAMPs play a beneficial role in anti-cancer therapy by interacting with the immune system. The molecular pathways involved in translocation of CRT to the cell surface and secretion of ATP from tumor cells undergoing ICD are being elucidated. However, it has also been shown that the same DAMPs could contribute to progression of cancer and promote resistance to anticancer treatments. In this review, we will critically evaluate the beneficial and detrimental roles of DAMPs in cancer therapy, focusing mainly on CRT, ATP and HMGB1

DAMPs and PDT-mediated photo-oxidative stress: exploring the unknown

Damage-associated molecular patterns (DAMPs) or cell death associated molecular patterns (CDAMPs) are a subset of endogenous intracellular molecules that are normally hidden within living cells but become either passively released by primary and secondary necrotic cells or actively exposed and secreted by the dying cells. Once released, DAMPs are sensed by the innate immune system and act as activators of antigen-presenting cells (APCs) to stimulate innate and adaptive immunity. Cancer cells dying in response to a subset of conventional anticancer modalities exhibit a particular composition of DAMPs at their cell surface, which has been recently shown to be vital for the stimulation of the host immune system and the control of residual disease. Photodynamic therapy (PDT) for cancer has long been shown to be capable of killing malignant cells and concomitantly stimulate the host immune system, properties that are likely linked to its ability of inducing exposure/release of certain DAMPs. PDT, by evoking oxidative stress at specific subcellular sites through the light activation of organelle-associated photosensitizers, may be unique in incorporating tumour cells destruction and antitumor immune response in one therapeutic paradigm. Here we review the current knowledge about mechanisms and signalling cascades leading to the exposure of DAMPs at the cell surface or promoting their release, the cell death mechanism associated to these processes and its immunological consequences. We also discuss how certain PDT paradigms may yield therapies that optimally stimulate the immune system and lead to the discovery of new DAMPs

A 3D cell death assay to quantitatively determine ferroptosis in spheroids

The failure of drug efficacy in clinical trials remains a big issue in cancer research. This is largely due to the limitations of two-dimensional (2D) cell cultures, the most used tool in drug screening. Nowadays, three-dimensional (3D) cultures, including spheroids, are acknowledged to be a better model of the in vivo environment, but detailed cell death assays for 3D cultures (including those for ferroptosis) are scarce. In this work, we show that a new cell death analysis method, named 3D Cell Death Assay (3DELTA), can efficiently determine different cell death types including ferroptosis and quantitatively assess cell death in tumour spheroids. Our method uses Sytox dyes as a cell death marker and Triton X-100, which efficiently permeabilizes all cells in spheroids, was used to establish 100% cell death. After optimization of Sytox concentration, Triton X-100 concentration and timing, we showed that the 3DELTA method was able to detect signals from all cells without the need to disaggregate spheroids. Moreover, in this work we demonstrated that 2D experiments cannot be extrapolated to 3D cultures as 3D cultures are less sensitive to cell death induction. In conclusion, 3DELTA is a more cost-effective way to identify and measure cell death type in 3D cultures, including spheroids.</jats:p

An emerging role for nanomaterials in increasing immunogenicity of cancer cell death

In the last decade, it has become clear that anti-cancer therapy is more successful when it can also induce an immunogenic form of cancer cell death (ICD). ICD is an umbrella term covering several cell death modalities, including apoptosis and necroptosis. In general, ICD is characterized by the emission of damage-associated molecular patterns (DAMPs) and/or cytokines/chemokines, leading to the induction of strong anti-tumor immune responses. In experimental cancer therapy, new observations indicate that the immunogenicity of dying cancer cells can be improved by the use of biomaterials. In this review, after a brief overview of the basic principles of the concept of ICD and discussion of the potential use of DAMPs as biomarkers of therapy efficacy, we discuss an emerging role of nanomaterials as a promising strategy to modulate the immunogenicity of cancer cell death. We address how nanocarriers can be used to increase the immunogenicity of ICD and then turn our attention to their dual action. Nanocarriers can be used to increase the immunogenicity of dying cancer cells and to reduce the side effects of chemotherapy. Future studies will show whether biomaterials are truly an optimal strategy to modulate the immunogenicity of dying cancer cells and will provide the insights needed for the development of novel treatment strategies for cancer

Classification of analytics, sensorics, and bioanalytics with polyelectrolyte multilayer capsules

Polyelectrolyte multilayer (PEM) capsules, constructed by LbL (layer-by-layer)-adsorbing polymers on sacrificial templates, have become important carriers due to multifunctionality of materials adsorbed on their surface or encapsulated into their interior. They have been also been used broadly used as analytical tools. Chronologically and traditionally, chemical analytics has been developed first, which has long been synonymous with all analytics. But it is not the only development. To the best of our knowledge, a summary of all advances including their classification is not available to date. Here, we classify analytics, sensorics, and biosensorics functionalities implemented with polyelectrolyte multilayer capsules and coated particles according to the respective stimuli and application areas. In this classification, three distinct categories are identified: (I) chemical analytics (pH; K+, Na+, and Pb2+ ion; oxygen; and hydrogen peroxide sensors and chemical sensing with surface-enhanced Raman scattering (SERS)); (II) physical sensorics (temperature, mechanical properties and forces, and osmotic pressure); and (III) biosensorics and bioanalytics (fluorescence, glucose, urea, and protease biosensing and theranostics). In addition to this classification, we discuss also principles of detection using the above-mentioned stimuli. These application areas are expected to grow further, but the classification provided here should help (a) to realize the wealth of already available analytical and bioanalytical tools developed with capsules using inputs of chemical, physical, and biological stimuli and (b) to position future developments in their respective fields according to employed stimuli and application areas

ER stress and inflammation

Accumulating evidence indicates that ER-stress-activated pathways, e.g. the unfolded protein response (UPR), lead to activation of various inflammatory processes, such as the acute-phase response (APR) and those instigated by transcriptional factors like NF-κB and AP-1. ER stress-mediated inflammation has been found to be associated with several diseases, such as obesity, type 2 diabetes, intestinal bowel disease and cancer. The role of ER stress-mediated inflammation is not straightforward as it can vary from disease-promoting/supporting to disease-controlling depending upon the cell type or disease in focus. This makes therapeutic targeting of ER stress-mediated inflammation very challenging and tough. In this chapter, we discuss the biology of ER stress-induced inflammation, its role in various diseases, and the possibility of targeting it for therapeutic purposes