A translational concept of immuno-radiobiology.

• Sustained radiation effects are mediated through cytotoxic CD8+ Tcells. • Radi-ation-damaged cells release HMGB1. • HMGB1 activates macrophages to local immuno-stimulation via TNF • TNF contributes to DC maturation triggering effective CD8+ Tcell responses • Radiation effect is boosted with removal of nega-tive feedback of immune reaction. • Removal of immunological feedback via check-point inhibitors or anti-TGF-β. • Func-tional integrity of APCs and Tcells essential for radiation long-term effects. • Dose escalating studies are re-quired to define radiation-induced immune modulation. Traditional concepts of radiobiology model the direct radiation-induced cellular cytotoxicity but are not focused on late and sustained effects of radiation. Recent experimental data show the close involvement of immunological processes. Based on systematic PubMed searches, experimental data on immunological radiation effects are summarized and analyzed in a non-quantitative descriptive manner to provide a translational perspective on the immuno-modulatory impact of radiation in cancer. Novel experimental findings document that sustained radiation effects are ultimately mediated through systemic factors such as cytotoxic CD8+ T cells and involve a local immuno-stimulation. Increased tumor infiltration of CD8+ T cell is a prerequisite for long-term radiation effects. CD8+ T cell depletion induces radio-resistance in experimental tumors. The proposed sequence of events involves radiation-damaged cells that release HMGB1, which activates macrophages via TLR4 to a local immuno-stimulation via TNF, which contributes to maturation of DCs. The mature DCs migrate to lymph nodes where they trigger effective CD8+ T cell responses. Radiation effects are boosted, when the physiological self-terminating negative feedback of immune reactions is antagonised via blocking of TGF-β or via checkpoint inhibition with involvement of CD8+ T cells as common denominator. The concept of immuno-radiobiology emphasizes the necessity for a functional integrity of APCs and T cells for the long-term effects of radiotherapy. Local irradiation at higher doses induces tumor infiltration of CD8+ T cells, which can be boosted by immunotherapy. More systematic research is warranted to better understand the immunological effects of escalating radiation doses. [ABSTRACT FROM AUTHOR]