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Adenosine can thwart antitumor immune responses elicited by radiotherapy

Therapeutic strategies alleviating protumor ADO activities

Adenosine kann Strahlentherapie-vermittelte Immunantworten gegen Tumore konterkarieren

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Abstract

Background

By studying the bioenergetic status we could show that the development of tumor hypoxia is accompanied, apart from myriad other biologically relevant effects, by a substantial accumulation of adenosine (ADO). ADO has been shown to act as a strong immunosuppressive agent in tumors by modulating the innate and adaptive immune system. In contrast to ADO, standard radiotherapy (RT) can either stimulate or abrogate antitumor immune responses. Herein, we present ADO-mediated mechanisms that may thwart antitumor immune responses elicited by RT.

Materials and methods

An overview of the generation, accumulation, and ADO-related multifaceted inhibition of immune functions, contrasted with the antitumor immune effects of RT, is provided.

Results

Upon hypoxic stress, cancer cells release ATP into the extracellular space where nucleotides are converted into ADO by hypoxia-sensitive, membrane-bound ectoenzymes (CD39/CD73). ADO actions are mediated upon binding to surface receptors, mainly A2A receptors on tumor and immune cells. Receptor activation leads to a broad spectrum of strong immunosuppressive properties facilitating tumor escape from immune control. Mechanisms include (1) impaired activity of CD4 + T and CD8 + T, NK cells and dendritic cells (DC), decreased production of immuno-stimulatory lymphokines, and (2) activation of Treg cells, expansion of MDSCs, promotion of M2 macrophages, and increased activity of major immunosuppressive cytokines. In addition, ADO can directly stimulate tumor proliferation and angiogenesis.

Conclusion

ADO mechanisms described can thwart antitumor immune responses elicited by RT. Therapeutic strategies alleviating tumor-promoting activities of ADO include respiratory hyperoxia or mild hyperthermia, inhibition of CD39/CD73 ectoenzymes or blockade of A2A receptors, and inhibition of ATP-release channels or ADO transporters.

Zusammenfassung

Hintergrund

Untersuchungen des bioenergetischen Status ergaben, dass Tumorhypoxie neben vielen anderen bedeutsamen biologischen Effekten zu einem starken Adenosinanstieg (ADO) im Tumorgewebe führt. ADO kann die immunologische Tumorabwehr im Gegensatz zur Strahlentherapie (RT), welche die Immunantwort gegen Tumoren sowohl stimulieren als auch inhibieren kann, erheblich einschränken. Dargestellt werden die ADO-vermittelten Mechanismen, die der durch RT ausgelösten Immunabwehr entgegenwirken.

Material und Methoden

Beschrieben werden die Bildung und Anreicherung von ADO im Tumorgewebe sowie dessen vielfältige Hemmwirkungen auf die immunologische Tumorabwehr in Gegenüberstellung zur RT-induzierten Immunstimulation.

Ergebnisse

Hypoxische Tumorzellen exportieren ATP in den Extrazellularraum, wo es durch die hypoxiegesteuerten, membranständigen Ektoenzyme CD39/CD73 abgebaut wird. Das gebildete ADO bindet an spezifische Membranrezeptoren von Immun- und Tumorzellen und löst dadurch die adenosinerge Signalkaskade aus. Diese hat starke immunsuppressive Wirkung sowohl (1) durch Hemmung von tumorinfiltrierenden CD4 + und CD8 + T-, NK- und dendritischen Zellen sowie immunstimulierender Lymphokinsekretion, als auch (2) durch Aktivierung von Treg- und myeloischen Vorläuferzellen (MDSCs), M2-Polarisation von Makrophagen und Sekretionssteigerung immunsuppressiver Zytokine. Darüber hinaus fördert ADO Tumorzellproliferation und Angiogenese.

Schlussfolgerung

Die ADO-vermittelte Immunsuppression wirkt der RT-induzierten Immunstimulation entgegen. Um eine ADO-bedingte Tumorevasion zu vermeiden bzw. abzuschwächen, stehen derzeit folgende Therapieoptionen zur Verfügung: Atmung sauerstoffreicher Gasgemische und/oder milde Hyperthermie, Hemmung der CD39/CD73-Ektoenzyme und A2A-Rezeptorblockade, Hemmung des ATP-Kanals bzw. ADO-Transporters.

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Abbreviations

ADO:

Adenosine

ADP:

Adenosine diphosphate

AMP:

Adenosine monophosphate

APC:

Antigen presenting cell

AR:

Adenosine receptor

ATM:

Ataxia telangiectasia mutant

ATP:

Adenosine triphosphate

bFGF:

Basic fibroblast growth factor

cAMP:

Cyclic adenosine monophosphate

CD39:

Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)

CD73:

Ecto 5’-nucleotidase

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

CXCL9:

Chemokine (C-X-C motif) ligand 9

CXCL10:

Chemokine (C-X-C motif) ligand 10

CXCL16:

Chemokine (C-X-C motif) ligand 16

DAMP:

Danger-associated molecule pattern

DC:

Dendritic cell

DNA:

Deoxyribonucleic acid

EC:

Endothelial cell

ENT-1:

Equilibrative nucleoside transporter 1 (ADO transporter)

ERK1/2:

Extracellular signal-regulated protein kinases 1 and 2

FAS:

Member of the TNF receptor family (CD95)

FoxP3:

Forkhead box P3

G-protein:

Guanine nucleotide-binding protein

HIF-1 α:

Hypoxia-inducible factor 1-alpha

HMGB1:

High mobility group box 1 protein

HPLC:

High-performance liquid chromatography

HSP:

Heat shock protein

ICAM-1:

Intercellular adhesion molecule 1 (CD54)

IC:

Immune cell

IFN-γ:

Interferon gamma

IL-1β/-2/-8/-12:

Interleukin 1 beta/-2/-8/-12

M1 cell:

Antitumor macrophage

M2 cell:

Pro-tumorigenic macrophage

mAb:

Monoclonal antibody

MDSC:

Myeloid-derived suppressor cells

MHC:

Major histocompatibility antigen (complex)

MICA/B:

MHC class I polypeptide-related sequence A/B

NK cell:

Natural killer cell

Panx-1:

Pannexin-1 (ATP-channel)

PD-1:

Programmed cell death 1 protein

PD-L1:

PD-1 ligand

POM-1:

Na-polyoxotungstate

RNA:

Ribonucleic acid

RT:

Radiotherapy

shRNA:

Short hairpin RNA

siRNA:

Small interfering RNA

TC:

Tumor cell

Teff:

Effector T cell

TGF-β:

Transforming growth factor beta

Th1:

Helper T cell

TLR-4/-7/-9:

Toll-like receptor -4/-7/-9

TNF-α:

Tumor necrosis factor-alpha

Treg:

Regulatory T cell

VEGF:

Vascular endothelial growth factor

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Acknowledgments

The authors would like to thank Anett Lange for her valuable help during preparation of this article.

This work was supported by EU-CELLEUROPE (315963); BMBF (Strahlenkompetenz, 02NUK038A; Innovative Therapies, 01GU0823; NSCLC, 16GW0030 and the DFG Cluster of Excellence: Munich Centre for Advanced Photonics). The research leading to these results has received funding from the Deutsche Forschungsgemeinschaft (DFG) under Grant Agreement No. SFB 824/2; INST 95/980-1 FUGG; INST 411/37-1 FUGG irradiation devices and the Helmholtz Zentrum München (HMGU), CCG—Innate Immunity in Tumor Biology.

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Authors and Affiliations

  1. Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM), Ismaninger Strasse 22, 81675, Munich, Germany

    Peter Vaupel M.A. &  Gabriele Multhoff

  2. Institute for innovative Radiotherapy (iRT), Experimental Immune Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany

    Gabriele Multhoff

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  1. Peter Vaupel M.A.
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Correspondence to Peter Vaupel M.A..

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P. Vaupel and G. Multhoff state that there are no conflicts of interest.

The manuscript does not include studies on humans or animals.

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Vaupel, P., Multhoff, G. Adenosine can thwart antitumor immune responses elicited by radiotherapy. Strahlenther Onkol 192, 279–287 (2016). https://doi.org/10.1007/s00066-016-0948-1

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