Immunogenic Cell Death, DAMPs and Prothymosin α as a Putative Anticancer Immune Response Biomarker

Abstract

The new and increasingly studied concept of immunogenic cell death (ICD) revealed a previously unknown perspective of the various regulated cell death (RCD) modalities, elucidating their immunogenic properties and rendering obsolete the notion that immune stimulation is solely the outcome of necrosis. A distinct characteristic of ICD is the release of danger-associated molecular patterns (DAMPs) by dying and/or dead cells. Thus, several members of the DAMP family, such as the well-characterized heat shock proteins (HSPs) HSP70 and HSP90, the high-mobility group box 1 protein and calreticulin, and the thymic polypeptide prothymosin α (proTα) and its immunoreactive fragment proTα(100–109), are being studied as potential diagnostic tools and/or possible therapeutic agents. Here, we present the basic aspects and mechanisms of both ICD and other immunogenic RCD forms; denote the role of DAMPs in ICD; and further exploit the relevance of human proTα and proTα(100–109) in ICD, highlighting their possible clinical applications. Furthermore, we present the preliminary results of our in vitro studies, which show a direct correlation between the concentration of proTα/proTα(100–109) and the levels of cancer cell apoptosis, induced by anticancer agents and γ-radiation.

Tumor growth inhibition and immune system activation following treatment with thorium-227 conjugates and PD-1 check-point inhibition in the MC-38 murine model

“…MC-38 is an immunogenic cell line that also expresses PD-L1 and as such is a good target for both check-point inhibition and TAT treatment (Figures 1A,B). The in vitro treatment with both PD-L1 TTC and isotype Th-227 conjugate induced equivalent amounts of cell death (Figure 1A) and upregulation of markers of immunologic cell death including the DAMPs HMGB1, CRT and HSPs (Figures 1C,D), known to have immunostimulatory effects in tumors (42)(43)(44)(45). Although there is no known antigen for the isotype antibody expressed on the tumor cells, it appears there is some non-specific binding to the MC-38 cell line, indicating that the antibody is not a true negative control.…”

Development and validation of prognostic index based on immunogenic cell death-related genes with melanoma

“…ICD inducer-treated tumor cells stimulate the exposure of tumor-associated antigens, known as damage-associated molecular patterns (DAMP) ( 11 ), including calreticulin. DAMP promotes dendritic cells maturation, activation of cytotoxic T lymphocytes and secretion of a variety of cytokines (interferon-I) ( 12 ). ICDs enable anti-tumor T cells and secretion of multiple cytokines to alter the tumor microenvironment, thereby enhancing the response to immunotherapy ( 13 ).…”

Belantamab mafodotin induces immunogenic cell death within 24 h post‐administration in newly diagnosed multiple myeloma patients

“…2 Recent in vitro and in vivo evidence in mice support that Belamaf promotes anti-myeloma activity through the induction of immunogenic cell death (ICD), 3 a type of regulated cell death (RCD), which may trigger immune stimulation by endogenous components released from dying or dead cells. 4 ICD is characterized by the extracellular release of danger-associated molecular patterns (DAMPs, else termed alarmins), endogenous immunogenic compounds which, in the presence of tumor antigens, act as adjuvants in the microenvironment of dying cells, and, after their binding to innate immune receptors on antigenpresenting cells (APC), they likely promote tumor antigen-reactive T cell immune responses. 5 Well-known DAMPs with immunostimulatory properties are calreticulin (CRT), the high mobility group box 1 protein (HMGB1), and prothymosin α (proTα) or its immunopotent fragment proTα(100-109).…”

“…In the early phases of ICD, CRT translocates to the cell membrane, where it acts as an "eat me" signal for phagocytes. 4,5 HMGB1 and proTα are nuclear proteins, which, in normal conditions, interact with various transcription factors and histones, having a key role in chromatin remodeling and transcription regulation. However, at later stages of ICD, extracellularly released HMGB1 may be captured by APCs, triggering the production of both proinflammatory and inflammatory cytokines.…”

“…However, at later stages of ICD, extracellularly released HMGB1 may be captured by APCs, triggering the production of both proinflammatory and inflammatory cytokines. [4][5][6] Similarly, during ICD, the truncated by activated caspases carboxy-terminal decapeptide proTα(100-109) is released, binds Toll-like receptor 4 on APCs and consequently stimulates T cell activation. 7,8 Herein, we evaluated for the first time the actual effect of ICD in newly diagnosed MM (NDMM) patients treated with Belamaf, by measuring the levels of the three DAMPs prior and after Belamaf administration.…”