Skip to main content
SpringerLink
Log in

Radiation with immunotherapy: an emerging combination for cancer treatment

  • Review
  • Published:
Journal of Radiation Oncology

Abstract

Ionizing radiation (RT) delivered to solid tumors is well known to induce immunological changes within the local tumor microenvironment as well as elicit systemic responses that promote antitumor immunity. These immunomodulatory effects of RT are produced by multiple processes that include increased tumor-associated antigen release, enhanced immunogenic cancer cell death, and upregulation of proinflammatory cytokines, which ultimately promote T cell priming and activation. RT can also modify the tumor microenvironment to facilitate immune effector cell recruitment, maturation, and activation. Given these properties, RT may augment the effect of modern cancer immunotherapies. This review outlines the fundamental immunogenic properties of RT and presents an overview of the clinical experience thus far that support the combination of RT with immunotherapy in cancer treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Kalbasi A, June CH, Hass N, Vapiwala N (2013) Radiation and immunotherapy: a synergistic combination. J Clin Invest 123:2756–63

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  2. Wersall PJ, Blomgren H, Pisa P, Lax I, Kalkner KM, Svedman C (2006) Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol 45:493–7

    Article  PubMed  Google Scholar 

  3. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S, Wolchok JD (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925–31

  4. Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, Massarelli E, Hong D, Naing A, Diab A, Gomez D, Ye H, Heymach J, Komaki R, Allison JP, Sharma P, Welsh JW (2014) Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res 2:831–8

  5. Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, Weichselbaum RR, Fu YX (2009) Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114:307–13

  6. 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 58:862–70

  7. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S (2009) Fractionated but not single-dose radiotherapy induced an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15:5379–88

  8. Takeshima T, Chamoto K, Wakita D, Ohkuri T, Togashi Y, Shirato H, Kitamura H, Nishimura T (2010) Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy. Cancer Res 70:2697–706

  9. Wasserman J, Blomgren H, Rotstein S, Petrini B, Hammarstrom S (1989) Immunosuppression in irradiated breast cancer patients: in vitro effect of cyclooxygenase inhibitors. Bull N Y Acad Med 65:36–44

  10. Tang C, Liao Z, Gomez D, Levy L, Zhuang Y, Gebremichael RA, Hong DS, Komaki R, Welsh JW (2014) Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol Biol Phys 89:1084–91

  11. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–64

    Article  PubMed  CAS  Google Scholar 

  12. Korman AJ, Peggs KS, Allison JP (2006) Checkpoint blockade in cancer immunotherapy. Adv Immunol 90:297–339

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–23

  14. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Novolumab versus docetaxel in advanced squamous-cell non-small cell lung cancer. New Eng J Med 373:123–35

  15. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. New Eng J Med 366:2455–65

  16. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Eng J Med 366:2443–54

  17. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New Eng J Med 373:23–34

  18. Schaue D, McBride WH. Opportunities and Challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol 2015; 10.1038/nrclinonc.2015.120

  19. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445–55

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Kapsenberg ML (2003) Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3:984–93

    Article  PubMed  CAS  Google Scholar 

  21. Reed JC (2006) Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol 3:388–98

    Article  PubMed  CAS  Google Scholar 

  22. Green DR, Ferguson T, Zitvogel L, Kroemer G (2009) Immunogenic and tolerogenic cell death. Nat Rev Immunol 9:353–63

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, André F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med 13:1050–9

  24. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nature Rev Immunol 8:59–73

    Article  CAS  Google Scholar 

  25. Torchinsky MB, Garaude J, Martin A, Blander JM (2009) Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature 458:78–82

    Article  PubMed  CAS  Google Scholar 

  26. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Métivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Med 13:54–61

  27. Golden EB, Frances D, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Forment SC (2014) Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 3:e28518

    Article  PubMed Central  PubMed  Google Scholar 

  28. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T et al (2012) The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 109:6662–7

  29. Vermeer DW, Spanos WC, Vermeer PD, Bruns AM, Lee KM, Lee JH (2013) Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer. Int J Cancer 133:120–9

  30. Marincola F, Jaffee E, Hicklin D, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273

    Article  PubMed  CAS  Google Scholar 

  31. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, Griekspoor A, Mesman E, Verreck FA, Spits H, Schlom J, van Veelen P, Neefjes JJ (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203:1259–71

  32. Jain RK (2013) Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 31:2205–18

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  PubMed  CAS  Google Scholar 

  34. Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Rev Cancer 5:263–74

    Article  CAS  Google Scholar 

  35. Allavenaa P, Sicaa A, Solinasa G, Portaa C, Mantovania A (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Critical Rev in Oncol/Hem 66:1–9

    Article  Google Scholar 

  36. Pollard JW (2004) Tumor-educated macrophages promote tumor progression and metastasis. Nat Rev Cancer 4:71–8

    Article  PubMed  CAS  Google Scholar 

  37. Znati CA, Rosenstein M, Boucher Y, Epperly MW, Bloomer WD, Jain RK (1996) Effect of radiation on interstitial fluid pressure and oxygenation in a human tumor xenograft. Cancer Res 56:964–8

    PubMed  CAS  Google Scholar 

  38. Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5:429–41

    Article  PubMed  CAS  Google Scholar 

  39. Demaria S, Formenti SC (2007) Sensors of ionizing radiation effects on the immunological microenvironment of cancer. Int J Rad Biol 83:819–25

    Article  PubMed  CAS  Google Scholar 

  40. 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 62:1462–70

    PubMed  CAS  Google Scholar 

  41. Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM (2005) Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol 174:7516–23

    Article  PubMed  CAS  Google Scholar 

  42. Hallahan D, Kuchibhotla J, Wyble C (1996) Cell adhesion molecules mediate radiation-induced leukocyte adhesion to the vascular endothelium. Cancer Res 56:5150–5

    PubMed  CAS  Google Scholar 

  43. Gaugler MH, Squiban C, van der Meeren A, Bertho JM, Vandamme M, Mouthon MA (1997) Late and persistent up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression by ionizing radiation in human endothelial cells in vitro. Int J Radiat Biol 72:201–9

    Article  PubMed  CAS  Google Scholar 

  44. Hallahan DE, Virudachalam S (1999) Accumulation of P-selectin in the lumen of irradiated blood vessels. Radiat Res 152:6–13

    Article  PubMed  CAS  Google Scholar 

  45. Filatenkov A, Baker J, Mueller AM, Kenkel J, Ahn GO, Dutt S, Zhang N, Kohrt H, Jensen K, Dejbakhsh-Jones S, Shizuru JA, Negrin RN, Engleman EG, Strober S (2015) Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res 21:3727–39

  46. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520(7547):373–7

  47. Crittenden M, Kohrt H, Levy R, Jones J, Camphausen K, Dicker A, Demaria S, Formenti S (2015) Current clinical trials testing combinations of immunotherapy and radiation. Semin Radiat Oncol 25:54–64

  48. Di Nicola M, Zappasodi R, Carlo-Stella C, Mortarini R, Pupa SM, Magni M, Devizzi L, Matteucci P, Baldassari P, Ravagnani F, Cabras A, Anichini A, Gianni AM (2009) Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot study. Blood 113:18–27

  49. Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R (1992) Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors. N Engl J Med 327:1209–15

  50. Li J, Song W, Czerwinski DK, Varghese B, Uematsu S, Akira S, Krieg AM, Levy R (2007) Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. J Immunol 179:2493–500

  51. Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, Kim YH, Hoppe RT, Knox SJ, Shin LK, Wapnir I, Tibshirani RJ, Levy R (2010) In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol 28:4324–32

  52. Kim YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, Morales A, Abdulla F, Xing L, Navi D, Tibshirani RJ, Advani RH, Lingala B, Shah S, Hoppe RT, Levy R (2012) In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 119:355–63

  53. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–16

  54. Fisher RI, Rosenberg SA, Fyfe G (2000) Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 6:S55–7

    PubMed  Google Scholar 

  55. Seung SK, Curti BD, Crittenden M, Walker E, Coffey T, Siebert JC, Miller W, Payne R, Glenn L, Bageac A, Urba WJ (2012) Phase 1 study of stereotactic body radiotherapy and interleukin-2--tumor and immunological responses. Sci Transl Med 4:137ra74

  56. Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, Friedman K, Ponzo F, Babb JS, Goldberg J, Demaria S, Formenti SC (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

  57. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006–17

  58. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, Scher HI, Chin K, Gagnier P, McHenry MB, Beer TM (2013) Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol 24:1813–21

  59. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR (2014) Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 15:700–12

  60. Jackson CM, Lim M, Drake CG (2014) Immunotherapy for brain cancer: recent progress and future promise. Clin Cancer Res 20:3651–9

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

Wen Jiang, Chad Tang, and Joe Chang report no conflict of interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Author information

Author notes

    Authors and Affiliations

    1. Department of Radiation Oncology, MD Anderson Cancer Center, Unit 97, 1515 Holcombe Blvd, Houston, TX, 77030, USA

      Wen Jiang, Chad Tang & Joe Y. Chang

    Authors
    1. Wen Jiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Chad Tang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Joe Y. Chang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Joe Y. Chang.

    Additional information

    Wen Jiang and Chad Tang contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Jiang, W., Tang, C. & Chang, J.Y. Radiation with immunotherapy: an emerging combination for cancer treatment. J Radiat Oncol 4, 331–338 (2015). https://doi.org/10.1007/s13566-015-0217-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13566-015-0217-4

    Keywords

    Search

    Navigation