An Overview on Immunogenic Cell Death in Cancer Biology and Therapy

Abstract

Immunogenic cell death (ICD) is a modality of regulated cell death that is sufficient to promote an adaptive immune response against antigens of the dying cell in an immunocompetent host. An important characteristic of ICD is the release and exposure of damage-associated molecular patterns, which are potent endogenous immune adjuvants. As the induction of ICD can be achieved with conventional cytotoxic agents, it represents a potential approach for the immunotherapy of cancer. Here, different aspects of ICD in cancer biology and treatment are reviewed.

Keywords: DAMPs; chemotherapy; immune system; immunotherapy; photodynamic therapy; radiotherapy.

Figure 1

Engagement of adaptive immune response after immunogenic cell death in a tumor. Chemotherapy, radiotherapy, and photodynamic therapy can induce immunogenic cell death (ICD), which is a programmed cell death accompanied by the exposure of damage-associated molecular patterns (DAMPs). This can occur, for instance, as a consequence of oxidative stress in the endoplasmic reticulum. Some DAMPs, such as heat-shock protein (HSP)70, HSP90, and calreticulin are exposed on the plasma membrane, while others such as adenosine triphosphate (ATP), high mobility group box 1 protein (HMGB1), C-X-C motif chemokine ligand 10 (CXCL10) and annexin A1 (ANXA-1) are released to the extracellular medium. DAMPs then activate pattern recognition receptors of dendritic cells (DCs) and other antigen-presenting cells. This culminates in the maturation of the DCs and in the recruitment and activation of T cells. In this way, ICD can trigger or boost an adaptive antitumor immune response.

Figure 2

Activation of responses to protein malformation. These three pathways—IRE1α (a), ATF6 (b) and PERK (c)—are activated in unfolded protein response (UPR) to cope with disturbances in protein folding and to restore endoplasmic reticulum homeostasis after stress. The phosphorylation of eIF2α is a hallmark of immunogenic cell death. Legend: ROS: reactive oxygen species; BiP: Binding immunoglobulin protein; ER: endoplasmic reticulum; IRE1α: inositol-requiring enzyme 1α; XBP1: X box-binding protein 1 mRNA; XBP1S: spliced X box-binding protein 1 mRNA; ATF6: activating transcription factor 6; PERK: protein kinase RNA-like endoplasmic reticulum kinase; ATF4: activating transcription factor 4; S1P: site-1 protease; S2P: site-1 protease; eIF2α: eukaryotic initiation factor 2α.

Figure 3

The induction of immunogenic cell death (ICD), the exposure of damage-associated molecular patterns (DAMPs), and the activation of antigen-presenting cells (APC) can be enhanced by delivery strategies based on nanotechnology.