Immunogenic Cell Death Induction by Ionizing Radiation

Abstract

Immunogenic cell death (ICD) is a form of regulated cell death (RCD) induced by various stresses and produces antitumor immunity via damage-associated molecular patterns (DAMPs) release or exposure, mainly including high mobility group box 1 (HMGB1), calreticulin (CRT), adenosine triphosphate (ATP), and heat shock proteins (HSPs). Emerging evidence has suggested that ionizing radiation (IR) can induce ICD, and the dose, type, and fractionation of irradiation influence the induction of ICD. At present, IR-induced ICD is mainly verified in vitro in mice and there is few clinical evidence about it. To boost the induction of ICD by IR, some strategies have shown synergy with IR to enhance antitumor immune response, such as hyperthermia, nanoparticles, and chemotherapy. In this review, we focus on the molecular mechanisms of ICD, ICD-promoting factors associated with irradiation, the clinical evidence of ICD, and immunogenic forms of cell death. Finally, we summarize various methods of improving ICD induced by IR.

Keywords: chemotherapy; damage-associated molecular patterns; ferroptosis; hyperthermia; immunogenic cell death; ionizing radiation; nanoparticles; necroptosis.

Figure 1

Mechanism of IR-driven ICD. Tumor cells release cDAMPs, chemokines, and tumor antigens following IR. Chemokines attract macrophages and immature DCs to tumor cells. cDAMPs like ATP, CRT, HSP70/90, and HMGB1 bind to corresponding receptors (P2RX7/P2RY2, CD91, CD40/CD91, and TLR4, respectively) on DCs leading to their activation. Recruited DCs can engulf and process tumor antigens. Mature DCs present tumor antigens to surface MHC-I molecules and then migrate to tumor-draining lymph nodes. There, DCs produce IL-6, IL-1β, TNF-α, and IFN-γ and cross-present antigens to boost T-cell differentiation to CTLs. CTLs can migrate to the tumor site and kill malignant cells by releasing perforin, granzyme B, or through the stimulation of the Fas/FasL pathway. ATP, Adenosine triphosphate; cDAMPs, Constitutive damage-associated molecular patterns; CRT, Calreticulin; CTL, Cytotoxic T lymphocyte; DC, Dendritic cell; Fas, Factor-related apoptosis; FasL, Factor-related apoptosis ligand; HMGB1, High mobility group box 1; HSP, Heat shock protein; ICD, Immunogenic cell death; IFN-γ, Type γ interferon; IL-1β, Interleukin-1β; IL-6, Interleukin-6; IR, Ionizing radiation; MHC I, Major histocompatibility complex class I; P2RX7, P2X purinoceptor 7; P2RY2, Purinergic receptor P2Y2; TCR, T-cell receptor; TLR4, Toll-like receptor 4; TNF-α, Tumor necrosis factor-α.