Radiotherapy as a New Player in Immuno-Oncology

Abstract

Recent development in radiation biology has revealed potent immunogenic properties of radiotherapy in cancer treatments. However, antitumor immune effects of radiotherapy are limited by the concomitant induction of radiation-dependent immunosuppressive effects. In the growing era of immunotherapy, combining radiotherapy with immunomodulating agents has demonstrated enhancement of radiation-induced antitumor immune activation that correlated with improved treatment outcomes. Yet, how to optimally deliver combination therapy regarding dose-fractionation and timing of radiotherapy is largely unknown. Future prospective testing to fine-tune this promising combination of radiotherapy and immunotherapy is warranted.

Keywords: cancer; combination therapy; dose-fractionation; immunotherapy; radiation; radiotherapy; timing.

Figure 1

Pro-immunogenic and immunosuppressive properties of radiation. Radiation promotes tumor immunogenicity by release of danger-associated molecular patterns (DAMPs) to attract and activate immune cells, translocation of calreticulin to the cell surface to serve as a phagocytotic signal, upregulation of death receptors and ligands (TRAIL, FAS, and DR 4/5), release of various pro-inflammatory cytokines, increase in MHC I expression to facilitate antigen presentation, and neoantigen formation. Low-dose radiation to the tumor vasculature can also induce ICAM-1 and E-selectin expression on endothelial cells to promote extravasation of immune cells into the tumor microenvironment (TME). On the other hand, immunosuppressive effects of radiation include lymphopenia due to cytotoxic effects of radiation on lymphocytes, proportional increase in Tregs, M2 polarization of macrophages, secretion of anti-inflammatory cytokine TGF-β, and induction of PD-L1 expression on tumor cells. Abbreviations: HMGB1 = high mobility group box 1; HSP = heat shock protein; ATP = adenosine triphosphate; TRAIL = tumor necrosis factor-related apoptosis-inducing ligand; DR4/5 = death receptor 4/5; IL-1β = interleukin 1β; TNF-α = tumor necrosis factor α; MHC I = major histocompatibility complex class I; ICAM-1 = intercellular adhesion molecule 1; Mφ2 = M2 macrophage; TGF-β = transforming growth factor β; PD-L1 = programmed death ligand 1.