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

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.

Keywords

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

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

Notes

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).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no competing interests.

References

  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013 CrossRefPubMedGoogle Scholar
  2. 2.
    Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer immunoediting and its three component phases–elimination, equilibrium and escape. Curr Opin Immunol 27:16–25. doi:10.1016/j.coi.2014.01.004 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148. doi:10.1016/j.immuni.2004.07.017 CrossRefPubMedGoogle Scholar
  4. 4.
    Kepp O, Senovilla L, Vitale I et al (2014) Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3:e955691. doi:10.4161/21624011.2014.955691 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Apetoh L, Ghiringhelli F, Tesniere A et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059. doi:10.1038/nm1622 CrossRefPubMedGoogle Scholar
  6. 6.
    Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Cremer I, Zitvogel L, Kroemer G, Galluzzi L (2014) Trial watch: chemotherapy with immunogenic cell death inducers. Oncoimmunology 3:e27878. doi:10.4161/onci.27878 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kroemer G, El-Deiry WS, Golstein P et al (2005) Classification of cell death: recommendations of the nomenclature committee on cell death. Cell Death Differ 12(Suppl 2):1463–1467. doi:10.1038/sj.cdd.4401724 CrossRefPubMedGoogle Scholar
  8. 8.
    Salomaa SI, Wright EG, Hildebrandt G, Kadhim MA, Little MP, Prise KM, Belyakov OV (2010) Editorial. Non-DNA targeted effects. Mutat Res 687:1–2. doi:10.1016/j.mrfmmm.2010.01.018 CrossRefPubMedGoogle Scholar
  9. 9.
    Hodge JW, Ardiani A, Farsaci B, Kwilas AR, Gameiro SR (2012) The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol 39:323–339. doi:10.1053/j.seminoncol.2012.02.006 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Frey B, Rubner Y, Kulzer L, Werthmoller N, Weiss EM, Fietkau R, Gaipl US (2014) Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol Immunother 63:29–36. doi:10.1007/s00262-013-1474-y CrossRefPubMedGoogle Scholar
  11. 11.
    Gaipl US, Multhoff G, Scheithauer H, Lauber K, Hehlgans S, Frey B, Rodel F (2014) Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy. Immunotherapy 6:597–610. doi:10.2217/imt.14.38 CrossRefPubMedGoogle Scholar
  12. 12.
    Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC (2004) Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58:862–870. doi:10.1016/j.ijrobp.2003.09.012 CrossRefPubMedGoogle Scholar
  13. 13.
    Werthmöller N, Frey B, Wunderlich R, Fietkau R, Gaipl US (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:e1761. doi:10.1038/cddis.2015.129 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714. doi:10.1038/nrm2970 CrossRefPubMedGoogle Scholar
  15. 15.
    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 24:589–602. doi:10.1016/j.ccr.2013.09.014 CrossRefPubMedGoogle Scholar
  16. 16.
    Garbi N, Arnold B, Gordon S, Hammerling GJ, Ganss R (2004) CpG motifs as proinflammatory factors render autochthonous tumors permissive for infiltration and destruction. J Immunol 172:5861–5869. doi:10.4049/jimmunol.172.10.5861 CrossRefPubMedGoogle Scholar
  17. 17.
    Frey B, Hehlgans S, Rödel F, Gaipl US (2015) Modulation of inflammation by low and high doses of ionizing radiation: implications for benign and malign diseases. Cancer Lett 368:230–237. doi:10.1016/j.canlet.2015.04.010 CrossRefPubMedGoogle Scholar
  18. 18.
    Witek M, Blomain ES, Magee MS, Xiang B, Waldman SA, Snook AE (2014) Tumor radiation therapy creates therapeutic vaccine responses to the colorectal cancer antigen GUCY2C. Int J Radiat Oncol Biol Phys 88:1188–1195. doi:10.1016/j.ijrobp.2013.12.043 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kulzer L, Rubner Y, Deloch L, Allgauer A, Frey B, Fietkau R, Dorrie J, Schaft N, Gaipl US (2014) Norm- and hypo-fractionated radiotherapy is capable of activating human dendritic cells. J Immunotoxicol 11:328–336. doi:10.3109/1547691x.2014.880533 CrossRefPubMedGoogle Scholar
  20. 20.
    Zeng J, See AP, Phallen J et al (2013) Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 86:343–349. doi:10.1016/j.ijrobp.2012.12.025 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15:5379–5388. doi:10.1158/1078-0432.ccr-09-0265 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ganss R, Ryschich E, Klar E, Arnold B, Hammerling GJ (2002) Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 62:1462–1470PubMedGoogle Scholar
  23. 23.
    Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX, Auh SL (2011) The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res 71:2488–2496. doi:10.1158/0008-5472.can-10-2820 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rubner Y, Wunderlich R, Ruhle PF et al (2012) How does ionizing irradiation contribute to the induction of anti-tumor immunity? Front Oncol 2:75. doi:10.3389/fonc.2012.00075 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wunderlich R, Ernst A, Rodel F, Fietkau R, Ott O, Lauber K, Frey B, Gaipl US (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 179:50–61. doi:10.1111/cei.12344 CrossRefPubMedGoogle Scholar
  26. 26.
    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899. doi:10.1016/j.cell.2010.01.025 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. doi:10.1038/nrc3239 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer Immunother Sci 342:1432–1433. doi:10.1126/science.342.6165.1432 Google Scholar
  29. 29.
    Eggermont AM, Maio M, Robert C (2015) Immune checkpoint inhibitors in melanoma provide the cornerstones for curative therapies. Semin Oncol 42:429–435. doi:10.1053/j.seminoncol.2015.02.010 CrossRefPubMedGoogle Scholar
  30. 30.
    Pandha H, Pawelec G (2015) Immune checkpoint targeting as anti-cancer immunotherapy: promises, questions, challenges and the need for predictive biomarkers at ASCO 2015. Cancer Immunol Immunother 64:1071–1074. doi:10.1007/s00262-015-1748-7 CrossRefPubMedGoogle Scholar
  31. 31.
    Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC (2005) Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 11:728–734PubMedGoogle Scholar
  32. 32.
    Verbrugge I, Hagekyriakou J, Sharp LL et al (2012) Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res 72:3163–3174. doi:10.1158/0008-5472.can-12-0210 CrossRefPubMedGoogle Scholar
  33. 33.
    Twyman-Saint Victor C, Rech AJ, Maity A et al (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–377. doi:10.1038/nature14292 CrossRefPubMedGoogle Scholar
  34. 34.
    Kim JE, Patel MA, Mangraviti A et al (2015) 143 the combination of anti-TIM-3 and anti-PD-1 checkpoint inhibitors with focused radiation resulted in a synergistic antitumor immune response in a preclinical glioma model. Neurosurgery 62(Suppl 1):212. doi:10.1227/01.neu.0000467105.60300.04 CrossRefGoogle Scholar
  35. 35.
    Frey B, Rubner Y, Wunderlich R, Weiss EM, Pockley AG, Fietkau R, Gaipl US (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
  36. 36.
    Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687–695. doi:10.1172/jci67313 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    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 74:5458–5468. doi:10.1158/0008-5472.can-14-1258 CrossRefPubMedGoogle Scholar
  38. 38.
    Barker CA, Postow MA (2014) Combinations of radiation therapy and immunotherapy for melanoma: a review of clinical outcomes. Int J Radiat Oncol Biol Phys 88:986–997. doi:10.1016/j.ijrobp.2013.08.035 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    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 16:795–803. doi:10.1016/s1470-2045(15)00054-6 CrossRefPubMedGoogle Scholar
  40. 40.
    Alexandrov LB, Nik-Zainal S, Wedge DC et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421. doi:10.1038/nature12477 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD (2014) Immune modulation in cancer with antibodies. Annu Rev Med 65:185–202. doi:10.1146/annurev-med-092012-112807 CrossRefPubMedGoogle Scholar
  42. 42.
    Philips GK, Atkins M (2015) Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. Int Immunol 27:39–46. doi:10.1093/intimm/dxu095 CrossRefPubMedGoogle Scholar
  43. 43.
    Kline J, Bishop MR (2015) Update on checkpoint blockade therapy for lymphoma. J Immunother Cancer 3:33. doi:10.1186/s40425-015-0079-8 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    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 6:162. doi:10.3389/fimmu.2015.00162 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Barker HE, Paget JT, Khan AA, Harrington KJ (2015) The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 15:409–425. doi:10.1038/nrc3958 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ngiow SF, McArthur GA, Smyth MJ (2015) Radiotherapy complements immune checkpoint blockade. Cancer Cell 27:437–438. doi:10.1016/j.ccell.2015.03.015 CrossRefPubMedGoogle Scholar
  47. 47.
    Frey B, Gaipl US (2015) Radio-immunotherapy: the focused beam expands. Lancet Oncol 16:742–743. doi:10.1016/s1470-2045(15)00055-8 CrossRefPubMedGoogle Scholar

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

Personalised recommendations