In situ vaccination caused by diverse irradiation-driven cell death programs

Abstract

Interest surrounding the effect of irradiation on immune activation has exponentially grown within the last decade. This includes work regarding mechanisms of the abscopal effect and the success achieved by combination of radiotherapy and immunotherapy. It is hypothesized that irradiation triggers the immune system to eliminate tumors by inducing tumor cells immunogenic cell death (ICD) in tumor cells. Activation of the ICD pathways can be exploited as an in situ vaccine. In this review, we provide fundamental knowledge of various forms of ICD caused by irradiation, describe the relationship between various cell death pathways and the immune activation effect driven by irradiation, and focus on the therapeutic value of exploiting these cell death programs in the context of irradiation. Furthermore, we summarize the immunomodulatory effect of different cell death programs on combinative radiotherapy and immunotherapy. In brief, differences in cell death programs significantly impact the irradiation-induced immune activation effect. Evaluating the transition between them will provide clues to develop new strategies for radiotherapy and its combination with immunotherapy.

Keywords: Cell death programs; immunotherapy; in situ vaccine; irradiation.

Figure 1

The “in situ vaccine” impact triggered by radiotherapy on tumor microenvironment. APC, Antigen-presenting cells; EVs, Extracellular vesicles; MPs, Microparticles; ATP, Adenosine triphosphate; HMGB1, High mobility group box 1; CRT, Calreticulin.

Figure 2

The mechanisms underlying radiotherapy-induced necroptosis. FASL, Fas ligand; TRAIL, Tumor necrosis factor related apoptosis-induced ligand; TRAILR, Tumor necrosis factor related apoptosis-induced ligand receptor; ZBP1, Z-DNA binding protein 1; RIPK3, RIP kinases 3; MLKL, mixed-lineage kinase domain-like protein.

Figure 3

Radiotherapy-induced pyroptosis in tumor cells, immune cells and endothelial cells. OTUD4, OTU deubiquitinase 4; AIM2, Absent in melanoma 2; NLRP3, NOD-like receptor thermal protein domain associated protein 3; RILI, Radiation-induced lung injury; RIII, Radiation-induced intestine injury.

Figure 4

The mechanisms underlying radiotherapy-induced ferroptosis. PUFA, Polyunsaturated fatty acid; ACSL4, Long-chain fatty acid-CoA ligase4; LPCAT3, Lysophosphatidylcholine Acyltransferase 3; GPX4, Glutathione peroxidase 4; ALOXs, Arachidonic acid lipoxygenases; POR, Cytochrome P450 Oxidoreductase.

Figure 5

The network interactions between different cell death pathways driven by radiotherapy. FADD, Fas Associated Via Death Domain; cFLIP, Cellular FLICE-inhibitory protein; tBID, truncated BID; ASC, Apoptosis-Associated Speck-Like Protein Containing A CARD.

Figure 6

Strategies and potential targets of redirecting apoptosis toward ICD-mediated forms. NLRP3, NOD-like receptor family members 3; TAK1, TGF-β activated kinase 1; RIPK1, Receptor-interacting protein kinases 1; RIPK3, Receptor-interacting protein kinases 3; ZBP1, Z-DNA binding protein 1; MLKL, Mixed-lineage kinase domain-like.