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

Protease/antiprotease network in allergy : the role of Staphylococcus aureus protease-like proteins

Staphylococcus aureus is being recognized as a major cofactor in atopic diseases such as atopic dermatitis, chronic rhinosinusitis with nasal polyps, and asthma. The understanding of the relationship between S aureus virulence factors and the immune system is continuously improving. Although the precise mechanism of the host's immune response adaptation to the variable secretion profile of S aureus strains continues to be a matter of debate, an increasing number of studies have reported on central effects of S aureus secretome in allergy. In this review, we discuss how colonization of S aureus modulates the innate and adaptive immune response, thereby predisposing the organism to allergic sensitization and disrupting immune tolerance in the airways of patients with asthma and chronic rhinosinusitis with nasal polyps. Next, we provide a critical overview of novel concepts dealing with S aureus in the initiation and persistence of chronic rhinosinusitis with nasal polyps and asthma. The role of the S aureus serine protease-like proteins in the initiation of a type 2 response and the contribution of the IL-33/ST2 signaling axis in allergic responses induced by bacterial allergens are discussed

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