Immunogenic cell death and DAMPs in cancer therapy

Abstract

Although it was thought that apoptotic cells, when rapidly phagocytosed, underwent a silent death that did not trigger an immune response, in recent years a new concept of immunogenic cell death (ICD) has emerged. The immunogenic characteristics of ICD are mainly mediated by damage-associated molecular patterns (DAMPs), which include surface-exposed calreticulin (CRT), secreted ATP and released high mobility group protein B1 (HMGB1). Most DAMPs can be recognized by pattern recognition receptors (PRRs). In this Review, we discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD.

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

“…We found that all AC-NP formulations, with the exception of mPEG AC-NPs, successfully captured neoantigens 24 (Figure 2c, Supplementary Table 1). Notably, AC-NPs also captured a number of damage associated molecular pattern proteins (DAMPs), a broad class of pro-inflammatory molecules that have been shown to potentiate immune response 27 . Notably, we found that our AC-NPs were capable of capturing histone proteins and alarmins (including HMGB1), both of which have been shown to enhance anti-tumor immune responses (Supplementary Table 1) 27 .…”

“…Notably, AC-NPs also captured a number of damage associated molecular pattern proteins (DAMPs), a broad class of pro-inflammatory molecules that have been shown to potentiate immune response 27 . Notably, we found that our AC-NPs were capable of capturing histone proteins and alarmins (including HMGB1), both of which have been shown to enhance anti-tumor immune responses (Supplementary Table 1) 27 . Our data confirm that AC-NPs capture a myriad of TDPAs that are released after radiotherapy.…”

Molecular mechanisms of ATP secretion during immunogenic cell death

“…Accumulating evidence now indicates that (at least some) anticancer agents actively stimulate tumor-specific immune responses, which in many cases account for long-term therapeutic successes. [1][2][3][4] Chemotherapy (as well as some forms of radiotherapy) can exert immunostimulatory effects via two alternative, although non-exclusive, mechanisms. First, some cytotoxic anticancer agents, including anthracyclines and oxaliplatin (OXA), are capable of triggering an immunogenic variant of apoptosis known as immunogenic cell death (ICD), 5,6 de facto converting dying cancer cells into a therapeutic vaccine.…”

“…2,11,12 Thus, the subcutaneous injection of cancer cells that are succumbing to ICD, but not of cells undergoing conventional apoptosis or necrosis, elicits a T-cell-mediated immune response protecting histocompatible mice against a subsequent challenge with tumor cells of the same type. 2,3,13 Of note, most inducers of apoptosis and necrosis fail to trigger ICD. However, a few chemotherapeutics, including anthracyclines, 7,8 OXA, 14 cyclophosphamide, 15 and -to some extent -microtubular inhibitors, 16 as well as cardiac glycosides, [17][18][19] potently do so.…”

“…ER stress culminates in the translocation of the ER chaperone calreticulin (CRT) to the cell surface, thereby generating an 'eat-me' signal for DCs. 3,22 Autophagy facilitates the release of ATP from dying cells, 23 constituting both a 'find-me' signal for the recruitment of DCs and their precursors 24 and a proinflammatory stimulus that -upon binding to the purinergic receptor P2RX7 -elicits the activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome within DCs and macrophages. 25,26 In addition, ICD is associated with the postmortem release of the non-histone chromatin-binding protein high-mobility group box 1 (HMGB1) into the extracellular space, allowing HMGB1 to bind Toll-like receptor 4 on DCs and thus stimulate their antigenpresenting functions.…”