Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death

Abstract

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called “damage-associated molecular patterns” (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis

“…[9][10][11][12] The ability of anticancer chemotherapy and radiotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of immunogenic cell death (ICD) and release of DAMPs, including heat shock proteins (HSPs), high-mobility group box 1 proteins (HMGB1), ATP and the endoplasmic reticulum (ER) chaperone calreticulin. 13,14 In this context, both HSP70 and HMGB1 appear to exert an immunostimulatory activity by promoting DC maturation through TLR4, which, in turn, leads to the induction of antigen-specific T cell-mediated antitumor immune responses. 15,16 In this regard, several studies highlight the importance of TLRs in the modulation of innate immune response in anticancer immunity.…”

Caspase-2 and oxidative stress underlie the immunogenic potential of high hydrostatic pressure-induced cancer cell death

“…1 However, accumulating evidence indicates that in response to certain chemotherapeutics (e.g., anthracyclines, mitoxantrone, oxaliplatin, or bortezomib), 2,3 ionizing irradiation, 4 oncolytic viruses, 5,6 and Hypericin-based photodynamic therapy (Hyp-PDT), 7,8 tumor cells can undergo an immunogenic form of apoptosis called "immunogenic cell death" (ICD) inducing an effective antitumor immune response in immunocompetent mice compared with vaccination of immunodeficient mice. 9,10 These findings demonstrate the important role of the immune system in the efficacy of anticancer therapy.…”

“…However, in absence of analysis for other ICD inducers, it is not yet known whether such a subdivision of danger signaling components is consistently applicable to other contexts and whether additional as-yet-undiscovered "private signaling components" mediating ecto-CALR, exist. 10 We previously described a novel physical modality, high hydrostatic pressure (HHP), inducing ICD in a wide spectrum of primary human tumor cells and human cancer cell lines. 20,21 The early danger signaling pathways activated by HHP in cancer cells are completely unknown.…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…9,20,21,260 Such knowledge has been instrumental for the development of a wide panel of therapeutic interventions that specifically aim at (re)establishing anticancer immunosurveillance (rather than merely causing the death of malignant cells), including peptide-based vaccination. 8,105,176,261-264 Unfortunately, it has soon become clear that the majority of immunotherapies developed so far is poorly active when employed as standalone therapeutic intervention, largely reflecting (1) natural and treatment-driven immunoediting, resulting in the selection of poorly immunogenic cancer cell populations; 115,265,266 and (2) the robust immunosuppression established by malignant cells, both locally and systemically. 267-269 In line with this notion, the vast majority of peptide-based vaccines tested in the clinic so far mediated limited, if any, therapeutic activity, despite being able to elicit tumor-targeting immune responses, at least to some degree.…”