Abstract
Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.
Highlights
In the response to radiation exposure, interactions with the immune system play an important role at multiple levels
high mobility group box 1 (HMGB1) induces increased tumor necrosis factor α (TNF-α) expression in human peripheral blood mononuclear cells, as well as TNF-α, IL-1α, IL-1β, IL-1RA, IL-6, IL-8, MIP-1α, and MIP-1β in human monocytes, but not IL-10 or IL-12 [113]. This indicates that inflammatory protein expression of immune cells may be in part due to stimulation via HMGB1 acting as damage-associated molecular patterns (DAMPs) after irradiation injury
The interactions between irradiated cancer as well as irradiated or bystander and abscopal immune cells are manifold. These radiation-induced interactions of immune cells in the tumor response are being elucidated for photonic radiation, but the effects of protons and carbon ions are largely unknown
Summary
In the response to radiation exposure, interactions with the immune system play an important role at multiple levels. Immune cells and their lymphoid and myeloid precursors and stem cells can be affected directly These effects are of major importance for acute medium- to high-dose exposures to ionizing radiation as the hematopoietic system. Radiation-induced bystander effects in the immune system encompass a complex network of signaling pathways, ranging from the DNA damage response of irradiated cells and unirradiated cells over the regulation of surface molecules on stationary body cells as well as circulating immune cells after radiation exposure and on the non-irradiated neighbors to the response of immune cells, due to direct or indirect intercellular communications of immune cell populations.
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