Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

Abstract

The concept of immunogenic cancer cell death (ICD), as originally observed during the treatment with several chemotherapeutics or ionizing irradiation, has revolutionized the view on the development of new anticancer therapies. ICD is defined by endoplasmic reticulum (ER) stress response, reactive oxygen species (ROS) generation, emission of danger-associated molecular patterns and induction of antitumor immunity. Here we describe known and emerging cancer cell death-inducing physical modalities, such as ionizing irradiation, ultraviolet C light, Photodynamic Therapy (PDT) with Hypericin, high hydrostatic pressure (HHP) and hyperthermia (HT), which have been shown to elicit effective antitumor immunity. We discuss the evidence of ICD induced by these modalities in cancer patients together with their applicability in immunotherapeutic protocols and anticancer vaccine development.

Keywords: ATP, Adenosine triphosphate; CRT, calreticulin; DAMPs, danger-associated molecular patterns; DC, dendritic cells; EGFR, endothelial growth factor receptor; ER, endoplasmic reticulum; HHP, high hydrostatic pressure, HMGB1, high-mobility group box 1; HSP, heat shock protein; HT, hyperthermia; Hyp-PDT, Hypericin-based Photodynamic therapy; ICD, immunogenic cell death; IFNγ, interferon-γ; NDV, Newcastle Disease Virus; ROS, reactive oxygen species; RT, radiotherapy; TLR, Toll-like receptor; UVC, ultraviolet C light; cancer immunotherapy; eIF2α, eukaryotic translation initiation factor 2α; high hydrostatic pressure; hyperthermia; immunogenic cell death; ionizing irradiation; photodynamic therapy with hypericin.

Figure 1.

Timeline of the most important discoveries in the field of immunogenic cell death. Abbreviations: ATP, Adenosine triphosphate; CRT, calreticulin; DC, dendritic cell; HMGB1, high mobility group box 1; HSP90, heat shock protein 90; Hyp-PDT, photodynamic therapy with hypericin; ICD, immunogenic cell death; LRP, lipoprotein receptor-related proteins; MyD88, myeloid differentiation primary response gene 88; TLR, toll like receptor; UVC, ultraviolet light C.

Figure 2.

A schematic representation of DC-based vaccine preparation using immunogenic HHP-killed tumor cells. Tumor cells treated with HHP (or other physical ICD-inducing modalities) expose various danger signals, so called DAMPs, in different stages of apoptosis. These DAMPs include calreticulin (CRT), heat shock proteins 70/90 (HSP70/90), HMGB1 and ATP. These molecules bind to respective cognate receptors like CD91 (for CRT/HSPs), TLR2/TLR4 (for HMGB1 or HSP70), P2RX7/P2RY2 (for ATP), respectively, on the cell surface of DCs. This leads to an enhanced engulfment of tumor cells and DC maturation characterized by upregulation of costimulatory molecules such as CD80, CD83, CD86 and HLA-DR, and by a distinct pro-inflammatory cytokine pattern. Activated DCs efficiently present tumor-specific antigens in the context of MHC class I and II molecules to T cells, inducing antitumor CD4⁺ and CD8⁺ T cell responses. Abbreviations: ATP, Adenosine triphosphate; CRT, calreticulin; CTL, cytotoxic T lymphocytes; DAMPs, danger-associated molecular patterns; DC, dendritic cell; HHP, high hydrostatic pressure; HMGB1, high mobility group box 1 HSP70, heat shock protein 70; HSP90, heat shock protein 90; ICD, immunogenic cell death; P2RX7, P2X purinoceptor 7; P2RY2, P2Y purinoceptor 2; RAGE, receptor for advanced glycation endproducts; TLR, toll like receptor.