title: Adenosine can thwart antitumor immune responses elicited by radiotherapy : Therapeutic strategies alleviating protumor ADO activities.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM), Ismaninger Strasse 22, 81675, Munich, Germany. peter.vaupel@tum.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Vaupel
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM), Ismaninger Strasse 22, 81675, Munich, Germany.|Institute for innovative Radiotherapy (iRT), Experimental Immune Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
mesh_terms: D000241:Adenosine / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology / Q000528:radiation effects; D019317:Evidence-Based Medicine; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology* / Q000528:radiation effects; D007155:Immunologic Factors / Q000276:immunology*; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology* / Q000532:radiotherapy*; D011878:Radiotherapy / Q000379:methods*; D016896:Treatment Outcome; D000072258:Tumor Hypoxia / Q000276:immunology / Q000528:radiation effects
chemical_list: D007155:Immunologic Factors; D000241:Adenosine
keywords: Adenosine; Immunostimulation; Immunosuppression; Radiotherapy; Tumor Hypoxia; Tumor Progression