Volume 25, Number 1

January 2015

Introduction

T

his issue of Seminars in Radiation Oncology focuses on the emerging research that encompasses the effects of ionizing radiation (IR) on the immune system. Although the finding that the degree of immunocompetence of the host influenced the response to radiotherapy dates back 35 years,1 it is only in the past 10 years that investigators have concentrated on studying the mechanisms behind these effects of radiation. During this decade, compelling results of research conducted at multiple institutions in different models have warranted revisiting the inflammatory response to radiation damage (both of the tumor and the exposed normal tissue), from a different angle, informed by the recent progress in understanding the immune response to tumors and the characteristic immunosuppressive microenvironment at the tumor site. Modern immunology has demonstrated that the process leading to the establishment of a detectable cancer and its progression is the result of a continuous interaction with the immune system of the host. The immune system is the natural guardian of tissue integrity, engaged in providing the necessary surveillance to maintain health and function. In fact, cancer can be considered a disease of the immune system, reflecting an inability to recognize and reject abnormal cells. Evidence is rapidly emerging about how radiotherapy contributes substantial signals at each stage of the cancer immune response. Figure 1 displays a modified version of the diagram by Chen and Mellman2 that summarizes the “Cancer-Immunity Cycle,” that is, the steps the immune system undertakes to successfully reject tumors. The image was modified to associate, for each stage of the immune response, references to some of the articles demonstrating the specific contribution of IR, as radiotherapy participates or contributes at each step of this physiological process.3-19 The articles that comprise this issue of Seminars aim at introducing the reader to this field and at stimulating interest to continue to follow this rapidly evolving area of radiobiology.20 The first article describes the inflammatory response induced by radiotherapy and introduces the reader to both the proimmunogenic and the immunosuppressive

http://dx.doi.org/10.1016/j.semradonc.2014.07.001 1053-4296/& 2015 Elsevier Inc. All rights reserved.

effects of IR. In the second article, Golden and Apetoh report a newly demonstrated capacity of IR, that of inducing immunogenic cell death, that is, a form of cellular demise capable of eliciting cross-priming of antigen-presenting cells. The third article concentrates on the recruitment and plasticity of immature myeloid cells, highlighting their common immune-suppressive effect after standard fractionated radiotherapy. It provides a general foundation to stimulate research to manipulate these generally immunosuppressive mediators. The remaining 4 articles exemplify testing different combinations of radiotherapy with available immunotherapy strategies. In most of these examples, radiotherapy is targeted to a localized tumor site and exploited for its capacity to induce immunogenic cell death and to provide relevant “danger signals.”21,22 Both components can alert the immune system and ideally recover an effective antitumor response. Preclinical experiments to study the combination of immunotherapy and radiotherapy require studying syngeneic, immune-competent experimental animals. In some instances, opposite results can be demonstrated when the immunologic status of the carrier is modified using nude mice and tumor xenografts.23 An obvious advantage of radiotherapy compared with chemotherapy agents capable of inducing immunogenic cell death24 is its localized effect on the target tumor, as opposed to the systemic toxicity that may be associated with a systemic type of immunotherapy. Importantly, in a setting of clinically ineffective systemic immunotherapy, adding radiation to a tumor site has demonstrated preclinically and in several clinical case reports to result in successful immune rejection of both the irradiated tumor and distant metastatic sites.25,26 This contribution of radiotherapy in enhancing tumor immunogenicity has been described as converting the irradiated cancer into an in situ, individualized vaccine. Finally, the last article summarizes some of the currently open clinical trials that, at 5 different academic institutions, are testing the feasibility and preliminary efficacy of combining radiotherapy and immunotherapy. Preliminary results from

1

S.C. Formenti

2

Release of cancer cell antigens (cancer cell death) (Ref. 3-4)

Cancer

Cancer antigen presentation (dendritic cells/APCs) (Ref. 5-7)

Killing of Immune and cancer cells (Ref. 19-20)

Lymph node

Recognition of cancer cells by T cells (CTLs, cancer cells) (Ref.16-18 )

Priming and activation (APCs & T cell) (Ref. 8-12)

Blood vessel

Infiltration of T cells into tumors (CTLs) (Ref. 15)

Trafficking of T cells to tumors (CTLs) (Ref. 13-14)

Figure 1 The cancer-immunity cycle. Each stage of the cycle radiation either contributes to or modifies the immune response to cancer, as exemplified by the articles referenced. (Modified with permission from Chen and Mellman.2)

these trials are encouraging and demonstrate successful translation of preclinical work. Silvia C. Formenti, MD Department of Radiation Oncology, New York University School of Medicine, New York, NY

References 1. Stone HB, Peters LJ, Milas L: Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J Natl Cancer Inst 63(5):1229-1235, 1979 2. Chen DS, Mellman I: Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1-10, 2013. [Review] 3. Apetoh L, Ghiringhelli F, Tesniere A: Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9):1050-1059, 2007 4. Golden E, Frances D, Pellicciotta I: Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 3: e28518, 2014 5. Chakravarty PK, Alfieri A, Thomas EK: Flt3-Ligand administration after radiation therapy prolongs survival in a murine model of metastatic lung cancer. Cancer Res 59(24):6028-6032, 1999 6. Nikitina EY, Gabrilovich DI: Combination of gamma-irradiation and dendritic cell administration induces a potent antitumor response in tumorbearing mice: approach to treatment of advanced stage cancer. Int J Cancer 94(6):825-833, 2001

7. Gulley JL, Arlen PM, Bastian N: Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 11(9):3353-3362, 2005 8. Lugade AA, Sorensen EW, Gerber SA: Radiation-induced IFNgamma production within the tumor microenvironment influences antitumor immunity. J Immunol 180(5):3132-3139, 2008 9. Demaria S, Kawashima N, Yang AM: Immune-mediated inhibition of metastases following treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 11(2 Pt 1):728-734, 2005 10. Reits EA, Hodge JW, Herberts CA: Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 203(5):1259-1271, 2006 11. Brody JD, Ai WZ, Czerwinski DK: In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol 28 (28):4324-4332, 2010 12. Burnette BC, Liang H, Lee Y: The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res 71(7):2488-2496, 2011 13. Matsumura S, Wang B, Kawashima N: Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol 181 (5):3099-3107, 2008 14. Klug F, Prakash H, Huber PE: Low-dose irradiation programs macrophage differentiation to an iNOSþ/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24(5):589-602, 2013 15. Chakraborty M, Abrams SI, Camphausen K: Irradiation of tumor cells upregulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J Immunol 170(12):6338-6347, 2003 16. Chakraborty M, Abrams SI, Coleman CN: External beam radiation of tumors alters phenotype of tumor cells to render them susceptible

Introduction

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to vaccine-mediated T-cell killing. Cancer Res 64(12):4328-4337, 2004 Newcomb EW, Demaria S, Lukyanov Y: The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas. Clin Cancer Res 12 (15):4730-4737, 2006 Demaria S, Ng B, Devitt M-L: Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58(3):862-870, 2004 Ruocco MG, Pilones KA, Kawashima N: Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves anti-tumor effects. J Clin Invest 122(10):3718-3730, 2012 Golden EB, Formenti SC: Is tumor (R)ejection by the immune system the “5th R” of radiobiology? Oncoimmunology 3(1), 2014

3 21. McBride WH, Chiang C-S, Olson JL: A sense of danger from radiation. Radiat Res 162(1):1-19, 2004 22. Formenti SC, Demaria S: Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 105:256-265, 2013 23. Ko A, Kanehisa A, Martins I: Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling. Cell Death Differ 21(1):92-99, 2014 24. Ma Y, Kepp O, Ghiringhelli F: Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol 22(3):113-124, 2010 25. Postow MA, Callahan MK, Barker CA: Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925-931, 2012 26. Golden EB, Demaria S, Schiff PB: An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 1(6):365-372, 2013

Seminars in Radiation Oncology. Introduction.

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