Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect

Tumor-targeted radiation occasionally elicits immune-mediated systemic tumor regression. Evidence of synergy between radiotherapy and immune checkpoint blockade (ICB) supports the concept of in situ vaccination by radiation, and ICB combinations together with an optimization of the radiation dose and fractionation offer paths to improved responses. Radiation alters the balance between immune-activating and -suppressive signals in the tumor microenvironment. Pathways involved in autoimmunity and microbial immunity are responsible for regulating the induction of type I interferon via cGAS/STING in irradiated tumors and are stimulated upon tumor cell irradiation and activation of the DNA damage response. Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects. Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects. from the Latin ab scopus (away from the target), this term indicates tumor regression seen outside of the field of radiation. key antigen-presenting cells for CD8 T cell activation that are dependent for ontogeny on the transcription factors IRF-8 and BATF3. a cytosolic DNA sensor that binds to microbial DNA as well as self-DNA and catalyzes cyclic GMP-AMP synthesis. endogenous molecules that functions as endogenous adjuvant once released by stressed or dying cells. high-fidelity DNA damage repair mechanism that occurs in S and G2 phases of the cell cycle using a sister chromatid as a template. a condition in which there is a lower-than-normal concentration of oxygen at the tissue level. therapeutic strategy based on the inhibition of immune checkpoint pathways that are in place to maintain self-tolerance and are co-opted by cancer to evade immune rejection. Currently approved drugs (antibodies) block immune checkpoint receptor cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) and its major ligand PD-L1. a form of cell death that is associated with the generation and release of DAMPs and cytokines that activate innate immune cells and promote the cross-presentation of antigens derived from the dying cells to T cells. error-prone repair of double-stranded DNA lesions that occurs in G1 phase of the cell cycle to attach the free DNA ends without a homologous template. energy deposited by ionizing radiation per unit mass, measured in gray (Gy): 1 Gy = 1 J/kg. a protein that resides on the outer leaflet of the endoplasmic reticulum and the endoplasmic reticulum-Golgi intermediate compartment and is activated by cyclic GMP-AMP produced by cGAS and by other cyclic dinucleotides of bacterial origin. STING activates the type I IFN and nuclear factor κB pathways. DNA exonuclease that degrades cytosolic single-stranded and double-stranded DNAs.