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

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

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.

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Abbreviations

Ab:

Antibody

Ag:

Antigen

APC:

Antigen-presenting cell

ATP:

Adenosine triphosphate

CpG:

Cytosine–guanine-rich motifs

CRT:

Calreticulin

CT:

Chemotherapy

CTLA-4:

Cytotoxic T lymphocyte antigen 4

DAMP:

Damage-associated molecular pattern

DC:

Dendritic cell

DNA:

Deoxyribonucleic acid

ER:

Endoplasmic reticulum

FDA:

US Food and Drug Administration

Flt3-L:

Fms-related tyrosine kinase 3 ligand

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

HMGB1:

High-mobility group box 1

Hsp70:

Heat shock protein 70

ICAM-1:

Intercellular adhesion molecule-1

IFN:

Interferon

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

MDSC:

Myeloid-derived suppressor cell

MHC:

Major histocompatibility complex

NSCLC:

Non-small cell lung cancer

PD-1:

Programmed cell death protein 1

ROS:

Reactive oxygen species

RT:

Radiotherapy

RT5:

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

TNF:

Tumor necrosis factor

X-ray:

Ionizing radiation

zVAD-fmk:

Z-Val-Ala-DL-Asp-FMK

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Acknowledgments

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).

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Authors and Affiliations

  1. Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsstraße 27, 91054, Erlangen, Germany

    Anja Derer, Benjamin Frey, Rainer Fietkau & Udo S. Gaipl

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  1. Anja Derer
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  2. Benjamin Frey
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Correspondence to Udo S. Gaipl.

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This paper is a Focussed Research Review based on a presentation given at the Fourth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2015), held in Ljubljana, Slovenia, 27th–30th April 2015. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Derer, A., Frey, B., Fietkau, R. et al. Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunol Immunother 65, 779–786 (2016). https://doi.org/10.1007/s00262-015-1771-8

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