Abstract
Background
Radiotherapy (RT) has been known for decades as a local treatment modality for malign and benign disease. In order to efficiently exploit the therapeutic potential of RT, an understanding of the immune modulatory properties of ionizing radiation is mandatory. These should be used for improvement of radioimmunotherapies for cancer in particular.
Methods
We here summarize the latest research and review articles about immune modulatory properties of RT, with focus on radiation dose and on combination of RT with selected immunotherapies. Based on the knowledge of the manifold immune mechanisms that are triggered by RT, thought-provoking impulse for multimodal radioimmunotherapies is provided.
Results
It has become obvious that ionizing radiation induces various forms of cell death and associated processes via DNA damage initiation and triggering of cellular stress responses. Immunogenic cell death (ICD) is of special interest since it activates the immune system via release of danger signals and via direct activation of immune cells. While RT with higher single doses in particular induces ICD, RT with a lower dose is mainly responsible for immune cell recruitment and for attenuation of an existing inflammation. The counteracting immunosuppression emanating from tumor cells can be overcome by combining RT with selected immunotherapies such as immune checkpoint inhibition, TGF-β inhibitors, and boosting of immunity with vaccination.
Conclusion
In order to exploit the full power of RT and thereby develop efficient radioimmunotherapies, the dose per fraction used in RT protocols, the fractionation, the quality, and the quantity of certain immunotherapies need to be qualitatively and chronologically well-matched to the individual immune status of the patient.
Zusammenfassung
Hintergrund
Strahlentherapie (ST) wird seit Jahrzehnten für die lokale Behandlung von benignen und malignen Krankheitsbildern verwendet. Um das weitreichende Potenzial der ST effizienter zu nutzen, ist ein besseres Verständnis der immunmodulierenden Eigenschaften der ionisierenden Strahlung essenziell. Dieses Wissen sollte auch für die Verbesserung von Strahlenimmuntherapien gegen Krebs verwendet werden.
Methoden
Wir fassen die neuste Literatur über die immunmodulierenden Eigenschaften der ST im Bezug zu einer bestimmten Dosis und in Kombination mit Immuntherapien zusammen. Basierend auf diesem Wissen über die vielfältigen immunologischen Mechanismen, die durch ST hervorgerufen werden, diskutieren wir neue multimodale Strahlenimmuntherapieansätze.
Ergebnisse
Es zeigte sich, dass ionisierende Strahlung verschiedene Zelltodesformen und assoziierte Prozesse als Folge von DNA-Schadens- und zellulären Stressantworten hervorruft. Dabei ist der immunogene Zelltod (IZT) von besonderem Interesse, da er das Immunsystem indirekt durch Freisetzung von Gefahrensignalen und durch direkte Aktivierung von Immunzellen aktiviert. Während ST mit höheren Einzeldosen pro Fraktion besonders IZT induziert, ist ST mit niedrigeren Dosen pro Fraktion hauptsächlich für die Rekrutierung von Immunzellen und die Abschwächung von vorherrschenden Entzündungen verantwortlich. Einer von den Tumorzellen ausgehenden Immunsuppression kann mit einer Kombination von ST und darauf angepassten Immuntherapien, wie z. B. Checkpoint-Inhibitoren, TGF-β-Inhibitoren oder Vakzinierung entgegengewirkt werden.
Schlussfolgerung
Um das volle Potenzial der ST auszuschöpfen, müssen Strahlenimmuntherapien entwickelt werden, bei denen verwendete ST-Einzeldosen, Fraktionierung sowie Qualität und Quantität bestimmter Immuntherapien qualitativ und chronologisch genau auf den individuellen Immunstatus des Patienten abgestimmt sind.
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Acknowledgements
This work was partially funded by the Bundesministerium für Bildung und Forschung (BMBF; GREWIS-alpha, 02NUK050E) and by the Research Training Group GRK1660 of the German Research Foundation (DFG).
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M. Rückert, L. Deloch, R. Fietkau, B. Frey, M. Hecht, and U.S. Gaipl declare that they have no competing interests.
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Michael Rückert and Lisa Deloch contributed equally.
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Rückert, M., Deloch, L., Fietkau, R. et al. Immune modulatory effects of radiotherapy as basis for well-reasoned radioimmunotherapies. Strahlenther Onkol 194, 509–519 (2018). https://doi.org/10.1007/s00066-018-1287-1
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DOI: https://doi.org/10.1007/s00066-018-1287-1