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Strahlentherapie und Onkologie

, Volume 194, Issue 6, pp 509–519 | Cite as

Immune modulatory effects of radiotherapy as basis for well-reasoned radioimmunotherapies

  • Michael Rückert
  • Lisa Deloch
  • Rainer Fietkau
  • Benjamin Frey
  • Markus Hecht
  • Udo S. Gaipl
Review Article

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.

Keywords

Ionising radiation Immunogenic cell death Inflammation Vaccination Immune checkpoint inhibition 

Immunmodulierende Eigenschaften von Radiotherapie als Basis für wohldurchdachte Radioimmuntherapien

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.

Schlüsselwörter

Ionisierende Strahlung Immunogener Zelltod Entzündung Impfung Immun-Checkpoint-Hemmung 

Notes

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).

Conflict of interest

M. Rückert, L. Deloch, R. Fietkau, B. Frey, M. Hecht, and U.S. Gaipl declare that they have no competing interests.

References

  1. 1.
    Wu Q, Allouch A, Martins I et al (2017) Modulating both tumor cell death and innate immunity is essential for improving radiation therapy effectiveness. Front Immunol 8:613CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lauber K, Ernst A, Orth M et al (2012) Dying cell clearance and its impact on the outcome of tumor radiotherapy. Front Oncol 2:116CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Castedo M, Perfettini JL, Roumier T et al (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23:2825–2837CrossRefPubMedGoogle Scholar
  4. 4.
    Deloch L, Derer A, Hartmann J et al (2016) Modern radiotherapy concepts and the impact of radiation on immune activation. Front Oncol 6:141CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Willems JJ, Arnold BP, Gregory CD (2014) Sinister self-sacrifice: the contribution of apoptosis to malignancy. Front Immunol 5:299CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Frey B, Schildkopf P, Rodel F et al (2009) AnnexinA5 renders dead tumor cells immunogenic—implications for multimodal cancer therapies. J Immunotoxicol 6:209–216CrossRefPubMedGoogle Scholar
  7. 7.
    Werthmoller N, Frey B, Wunderlich R et al (2015) Modulation of radiochemoimmunotherapy-induced B16 melanoma cell death by the pan-caspase inhibitor zVAD-fmk induces anti-tumor immunity in a HMGB1-, nucleotide- and T‑cell-dependent manner. Cell Death Dis 6:e1761CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kaczmarek A, Vandenabeele P, Krysko DV (2013) Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38:209–223CrossRefPubMedGoogle Scholar
  9. 9.
    Muth C, Rubner Y, Semrau S et al (2016) Primary glioblastoma multiforme tumors and recurrence: comparative analysis of the danger signals HMGB1, HSP70, and calreticulin. Strahlenther Onkol 192:146–155CrossRefPubMedGoogle Scholar
  10. 10.
    Lu C, Xie C (2016) Radiation-induced autophagy promotes esophageal squamous cell carcinoma cell survival via the LKB1 pathway. Oncol Rep 35:3559–3565CrossRefPubMedGoogle Scholar
  11. 11.
    Chiu HW, Lin SW, Lin LC et al (2015) Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6. Cancer Lett 365:229–239CrossRefPubMedGoogle Scholar
  12. 12.
    Citrin DE (2017) Recent developments in radiotherapy. N Engl J Med 377:1065–1075CrossRefPubMedGoogle Scholar
  13. 13.
    Kepp O, Senovilla L, Vitale I et al (2014) Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3:e955691CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Matzinger P (2002) The danger model: a renewed sense of self. Science 296:301–305CrossRefPubMedGoogle Scholar
  15. 15.
    Gaipl US, Multhoff G, Scheithauer H et al (2014) Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy. Immunotherapy 6:597–610CrossRefPubMedGoogle Scholar
  16. 16.
    Shevtsov M, Multhoff G (2016) Heat shock protein-peptide and HSP-based immunotherapies for the treatment of cancer. Front Immunol 7:171PubMedPubMedCentralGoogle Scholar
  17. 17.
    Stangl S, Tontcheva N, Sievert W et al (2017) Heat shock protein 70 and tumor-infiltrating NK cells as prognostic indicators for patients with squamous cell carcinoma of the head and neck after radiochemotherapy: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Int J Cancer.  https://doi.org/10.1002/ijc.31213 PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Specht HM, Ahrens N, Blankenstein C et al (2015) Heat Shock Protein 70 (Hsp70) peptide activated Natural Killer (NK) cells for the treatment of patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx)—from preclinical studies to a clinical phase II trial. Front Immunol 6:162CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Garg AD, Galluzzi L, Apetoh L et al (2015) Molecular and translational classifications of DAMPs in immunogenic cell death. Front Immunol 6:588CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Reits EA, Hodge JW, Herberts CA et al (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203:1259–1271CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Frey B, Rubner Y, Kulzer L et al (2014) Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol Immunother 63:29–36CrossRefPubMedGoogle Scholar
  22. 22.
    Galluzzi L, Buque A, Kepp O et al (2017) Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 17:97–111CrossRefPubMedGoogle Scholar
  23. 23.
    Wennerberg E, Lhuillier C, Vanpouille-Box C et al (2017) Barriers to radiation-induced in situ tumor vaccination. Front Immunol 8:229CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bouquet F, Pal A, Pilones KA et al (2011) TGFbeta1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res 17:6754–6765CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Deng L, Liang H, Burnette B et al (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687–695CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jobling MF, Mott JD, Finnegan MT et al (2006) Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res 166:839–848CrossRefPubMedGoogle Scholar
  27. 27.
    Vanpouille-Box C, Diamond JM, Pilones KA et al (2015) TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res 75:2232–2242CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Vanpouille-Box C, Alard A, Aryankalayil MJ et al (2017) DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 8:15618CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kang J, Demaria S, Formenti S (2016) Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer 4:51CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ni L, Dong C (2017) New checkpoints in cancer immunotherapy. Immunol Rev 276:52–65CrossRefPubMedGoogle Scholar
  31. 31.
    Dong H, Strome SE, Salomao DR et al (2002) Tumor-associated B7-H1 promotes T‑cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800CrossRefPubMedGoogle Scholar
  32. 32.
    Derer A, Spiljar M, Baumler M et al (2016) Chemoradiation increases PD-L1 expression in certain melanoma and glioblastoma cells. Front Immunol 7:610CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Dovedi SJ, Adlard AL, Lipowska-Bhalla G et al (2014) Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74:5458–5468CrossRefPubMedGoogle Scholar
  34. 34.
    Twyman-Saint Victor C, Rech AJ, Maity A et al (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–377CrossRefPubMedGoogle Scholar
  35. 35.
    Derer A, Deloch L, Rubner Y et al (2015) Radio-immunotherapy-induced immunogenic cancer cells as basis for induction of systemic anti-tumor immune responses—pre-clinical evidence and ongoing clinical applications. Front Immunol 6:505CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Golden EB, Chhabra A, Chachoua A et al (2015) Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 16:795–803CrossRefPubMedGoogle Scholar
  37. 37.
    Frey B, Gaipl US (2015) Radio-immunotherapy: the focused beam expands. Lancet Oncol 16:742–743CrossRefPubMedGoogle Scholar
  38. 38.
    Rodel F, Fournier C, Wiedemann J et al (2017) Basics of radiation biology when treating hyperproliferative benign diseases. Front Immunol 8:519CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Frey B, Hehlgans S, Rodel F et al (2015) Modulation of inflammation by low and high doses of ionizing radiation: implications for benign and malign diseases. Cancer Lett 368:230–237CrossRefPubMedGoogle Scholar
  40. 40.
    Rodel F, Frey B, Gaipl U et al (2012) Modulation of inflammatory immune reactions by low-dose ionizing radiation: molecular mechanisms and clinical application. Curr Med Chem 19:1741–1750CrossRefPubMedGoogle Scholar
  41. 41.
    Wunderlich R, Ernst A, Rodel F et al (2015) Low and moderate doses of ionizing radiation up to 2 Gy modulate transmigration and chemotaxis of activated macrophages, provoke an anti-inflammatory cytokine milieu, but do not impact upon viability and phagocytic function. Clin Exp Immunol 179:50–61CrossRefPubMedGoogle Scholar
  42. 42.
    Large M, Hehlgans S, Reichert S et al (2015) Study of the anti-inflammatory effects of low-dose radiation: the contribution of biphasic regulation of the antioxidative system in endothelial cells. Strahlenther Onkol 191:742–749CrossRefPubMedGoogle Scholar
  43. 43.
    Rodel F, Hofmann D, Auer J et al (2008) The anti-inflammatory effect of low-dose radiation therapy involves a diminished CCL20 chemokine expression and granulocyte/endothelial cell adhesion. Strahlenther Onkol 184:41–47CrossRefPubMedGoogle Scholar
  44. 44.
    Lodermann B, Wunderlich R, Frey S et al (2012) Low dose ionising radiation leads to a NF-kappaB dependent decreased secretion of active IL-1beta by activated macrophages with a discontinuous dose-dependency. Int J Radiat Biol 88:727–734CrossRefPubMedGoogle Scholar
  45. 45.
    Ott OJ, Jeremias C, Gaipl US et al (2015) Radiotherapy for benign achillodynia. Long-term results of the Erlangen Dose Optimization Trial. Strahlenther Onkol 191:979–984CrossRefPubMedGoogle Scholar
  46. 46.
    Ott OJ, Jeremias C, Gaipl US et al (2014) Radiotherapy for benign calcaneodynia: long-term results of the Erlangen Dose Optimization (EDO) trial. Strahlenther Onkol 190:671–675CrossRefPubMedGoogle Scholar
  47. 47.
    Ott OJ, Hertel S, Gaipl US et al (2014) The Erlangen Dose Optimization Trial for radiotherapy of benign painful shoulder syndrome. Long-term results. Strahlenther Onkol 190:394–398CrossRefPubMedGoogle Scholar
  48. 48.
    Ott OJ, Hertel S, Gaipl US et al (2014) The Erlangen Dose Optimization trial for low-dose radiotherapy of benign painful elbow syndrome. Long-term results. Strahlenther Onkol 190:293–297CrossRefPubMedGoogle Scholar
  49. 49.
    Ruhle PF, Wunderlich R, Deloch L et al (2017) Modulation of the peripheral immune system after low-dose radon spa therapy: detailed longitudinal immune monitoring of patients within the RAD-ON01 study. Autoimmunity 50:133–140CrossRefPubMedGoogle Scholar
  50. 50.
    Cucu A, Shreder K, Kraft D et al (2017) Decrease of markers related to bone erosion in serum of patients with musculoskeletal disorders after serial low-dose radon spa therapy. Front Immunol 8:882CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Asur R, Butterworth KT, Penagaricano JA et al (2015) High dose bystander effects in spatially fractionated radiation therapy. Cancer Lett 356:52–57CrossRefPubMedGoogle Scholar
  52. 52.
    Herskind C, Ma L, Liu Q et al (2017) Biology of high single doses of IORT: RBE, 5 R’s, and other biological aspects. Radiat Oncol 12:24CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ghita M, Coffey CB, Butterworth KT et al (2016) Impact of fractionation on out-of-field survival and DNA damage responses following exposure to intensity modulated radiation fields. Phys Med Biol 61:515–526CrossRefPubMedGoogle Scholar
  54. 54.
    Burnette BC, Liang H, Lee Y et al (2011) The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71:2488–2496CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Demaria O, De Gassart A, Coso S et al (2015) STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci USA 112:15408–15413CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Derer A, Frey B, Fietkau R et al (2016) Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunol Immunother 65:779–786CrossRefPubMedGoogle Scholar
  57. 57.
    Klug F, Prakash H, Huber PE et al (2013) Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24:589–602CrossRefPubMedGoogle Scholar
  58. 58.
    Frey B, Rubner Y, Wunderlich R et al (2012) Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation—implications for cancer therapies. Curr Med Chem 19:1751–1764CrossRefPubMedGoogle Scholar
  59. 59.
    Vanpouille-Box C, Pilones KA, Wennerberg E et al (2015) In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine 33:7415–7422CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Frey B, Rückert M, Deloch L et al (2017) Immunomodulation by ionizing radiation—impact for design of radio-immunotherapies and for treatment of inflammatory diseases. Immunol Rev 280(1):231–248.  https://doi.org/10.1111/imr.12572 CrossRefPubMedGoogle Scholar
  61. 61.
    Sahin U, Derhovanessian E, Miller M et al (2017) Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547:222–226CrossRefPubMedGoogle Scholar
  62. 62.
    Yarchoan M, Johnson BA 3rd, Lutz ER et al (2017) Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer 17:569CrossRefPubMedGoogle Scholar
  63. 63.
    Weiss EM, Wunderlich R, Ebel N et al (2012) Selected anti-tumor vaccines merit a place in multimodal tumor therapies. Front Oncol 2:132CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Liu R, Luo F, Liu X et al (2016) Biological response modifier in cancer immunotherapy. Adv Exp Med Biol 909:69–138CrossRefPubMedGoogle Scholar
  65. 65.
    Eckert F, Jelas I, Oehme M et al (2017) Tumor-targeted IL-12 combined with local irradiation leads to systemic tumor control via abscopal effects in vivo. Oncoimmunology 6:e1323161CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Yang QY, Yang JD, Wang YS (2017) Current strategies to improve the safety of chimeric antigen receptor (CAR) modified T cells. Immunol Lett 190:201–205CrossRefPubMedGoogle Scholar
  67. 67.
    Fournier C, Martin F, Zitvogel L et al (2017) Trial watch: adoptively transferred cells for anticancer immunotherapy. Oncoimmunology 6:e1363139CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    van der Burg SH, Arens R, Ossendorp F et al (2016) Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer 16:219–233CrossRefPubMedGoogle Scholar
  69. 69.
    Loi M, Desideri I, Greto D et al (2017) Radiotherapy in the age of cancer immunology: current concepts and future developments. Crit Rev Oncol Hematol 112:1–10CrossRefPubMedGoogle Scholar
  70. 70.
    Harjes U (2017) Tumour vaccines: personal training by vaccination. Nat Rev Cancer 17:451–451CrossRefPubMedGoogle Scholar
  71. 71.
    Muenst S, Soysal SD, Tzankov A et al (2015) The PD-1/PD-L1 pathway: biological background and clinical relevance of an emerging treatment target in immunotherapy. Expert Opin Ther Targets 19:201–211CrossRefPubMedGoogle Scholar
  72. 72.
    Le DT, Durham JN, Smith KN et al (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–413CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Topalian SL, Taube JM, Anders RA et al (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Weichselbaum RR, Liang H, Deng L et al (2017) Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 14(6):365–379.  https://doi.org/10.1038/nrclinonc.2016.211 CrossRefPubMedGoogle Scholar
  77. 77.
    Abuodeh Y, Venkat P, Kim S (2016) Systematic review of case reports on the abscopal effect. Curr Probl Cancer 40:25–37CrossRefPubMedGoogle Scholar
  78. 78.
    Demaria S, Ng B, Devitt ML et al (2004) Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58:862–870CrossRefPubMedGoogle Scholar
  79. 79.
    Zheng W, Skowron KB, Namm JP et al (2016) Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance. Oncotarget 7:43039–43051PubMedPubMedCentralGoogle Scholar
  80. 80.
    Dewan MZ, Galloway AE, Kawashima N et al (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15:5379–5388CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Frey B, Rückert M, Weber J et al (2017) Hypofractionated irradiation has immune stimulatory potential and induces a timely restricted infiltration of immune cells in colon cancer tumors. Front Immunol 8:231CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Hettich M, Lahoti J, Prasad S, Niedermann G (2016) Checkpoint Antibodies but not T Cell-Recruiting Diabodies Effectively Synergize with TIL-Inducing γ-Irradiation. Cancer Res 76:4673–4683CrossRefPubMedGoogle Scholar
  83. 83.
    Belka C, Ottinger H, Kreuzfelder E et al (1999) Impact of localized radiotherapy on blood immune cells counts and function in humans. Radiother Oncol 50:199–204CrossRefPubMedGoogle Scholar
  84. 84.
    Heylmann D, Rodel F, Kindler T et al (2014) Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells. Biochim Biophys Acta 1846:121–129PubMedGoogle Scholar
  85. 85.
    Sage EK, Schmid TE, Geinitz H et al (2017) Effects of definitive and salvage radiotherapy on the distribution of lymphocyte subpopulations in prostate cancer patients. Strahlenther Onkol 193:648–655CrossRefPubMedGoogle Scholar
  86. 86.
    van Meir H, Nout RA, Welters MJ et al (2017) Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients. Oncoimmunology 6:e1267095CrossRefPubMedGoogle Scholar
  87. 87.
    Frey B, Ruckert M, Deloch L et al (2017) Immunomodulation by ionizing radiation-impact for design of radio-immunotherapies and for treatment of inflammatory diseases. Immunol Rev 280:231–248CrossRefPubMedGoogle Scholar
  88. 88.
    Ruhle PF, Goerig N, Wunderlich R et al (2017) Modulations in the peripheral immune system of glioblastoma patient is connected to therapy and tumor progression-A case report from the IMMO-GLIO-01 trial. Front Neurol 8:296CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Rühle PF, Fietkau R, Gaipl US et al (2016) Development of a modular assay for detailed immunophenotyping of peripheral human whole blood samples by multicolor flow cytometry. Int J Mol Sci 17(8):E1316.  https://doi.org/10.3390/ijms17081316 CrossRefPubMedGoogle Scholar
  90. 90.
    Karakhanova S, Ryschich E, Mosl B et al (2015) Prognostic and predictive value of immunological parameters for chemoradioimmunotherapy in patients with pancreatic adenocarcinoma. Br J Cancer 112:1027–1036CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Michael Rückert
    • 1
  • Lisa Deloch
    • 1
  • Rainer Fietkau
    • 1
  • Benjamin Frey
    • 1
  • Markus Hecht
    • 1
  • Udo S. Gaipl
    • 1
  1. 1.Department of Radiation OncologyUniversitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)ErlangenGermany

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