Cancer Immunology, Immunotherapy

, Volume 65, Issue 7, pp 779–786 | Cite as

Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors

  • Anja Derer
  • Benjamin Frey
  • Rainer Fietkau
  • Udo S. Gaipl
Focussed Research Review


Radiotherapy (RT) utilizes the DNA-damaging properties of ionizing radiation to control tumor growth and ultimately kill tumor cells. By modifying the tumor cell phenotype and the tumor microenvironment, it may also modulate the immune system. However, out-of-field reactions of RT mostly assume further immune activation. Here, the sequence of the applications of RT and immunotherapy is crucial, just as the dose and fractionation may be. Lower single doses may impact on tumor vascularization and immune cell infiltration in particular, while higher doses may impact on intratumoral induction and production of type I interferons. The induction of immunogenic cancer cell death seems in turn to be a common mechanism for most RT schemes. Dendritic cells (DCs) are activated by the released danger signals and by taking up tumor peptides derived from irradiated cells. DCs subsequently activate T cells, a process that has to be tightly controlled to ensure tolerance. Inhibitory pathways known as immune checkpoints exist for this purpose and are exploited by tumors to inhibit immune responses. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T cells are two major checkpoints. The biological concepts behind the findings that RT in combination with anti-CTLA-4 and/or anti-PD-L1 blockade stimulates CD8+ T cell-mediated anti-tumor immunity are reviewed in detail. On this basis, we suggest clinically significant combinations and sequences of RT and immune checkpoint inhibition. We conclude that RT and immune therapies complement one another.


Radiotherapy Immunotherapy Immunogenic cancer cell death Immune checkpoint inhibitors Out-of-field effect CITIM 2015 







Antigen-presenting cell


Adenosine triphosphate


Cytosine–guanine-rich motifs






Cytotoxic T lymphocyte antigen 4


Damage-associated molecular pattern


Dendritic cell


Deoxyribonucleic acid


Endoplasmic reticulum


US Food and Drug Administration


Fms-related tyrosine kinase 3 ligand


Granulocyte-macrophage colony-stimulating factor


High-mobility group box 1


Heat shock protein 70


Intercellular adhesion molecule-1






Inducible nitric oxide synthase


Myeloid-derived suppressor cell


Major histocompatibility complex


Non-small cell lung cancer


Programmed cell death protein 1


Reactive oxygen species




Rat insulin promoter (RIP)1-Tag5 tumor mouse model


Tumor necrosis factor


Ionizing radiation





This work was partially funded by the German Federal Ministry of Education and Research (BMBF; m4 Cluster, 16EX1021R and GREWIS, 02NUK017G) and the European Commission (DoReMi, European Atomic Energy Community’s Seventh Framework Programme (FP7/2007-2011) under Grant Agreement No. 249689).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no competing interests.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Anja Derer
    • 1
  • Benjamin Frey
    • 1
  • Rainer Fietkau
    • 1
  • Udo S. Gaipl
    • 1
  1. 1.Department of Radiation Oncology, Universitätsklinikum ErlangenFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)ErlangenGermany

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