The confluence of stereotactic ablative radiotherapy and tumor immunology

Steven Eric Finkelstein, Robert Timmerman, William H McBride, Dörthe Schaue, Sarah E Hoffe, Constantine A Mantz, George D Wilson, Steven Eric Finkelstein, Robert Timmerman, William H McBride, Dörthe Schaue, Sarah E Hoffe, Constantine A Mantz, George D Wilson

Abstract

Stereotactic radiation approaches are gaining more popularity for the treatment of intracranial as well as extracranial tumors in organs such as the liver and lung. Technology, rather than biology, is driving the rapid adoption of stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), in the clinic due to advances in precise positioning and targeting. Dramatic improvements in tumor control have been demonstrated; however, our knowledge of normal tissue biology response mechanisms to large fraction sizes is lacking. Herein, we will discuss how SABR can induce cellular expression of MHC I, adhesion molecules, costimulatory molecules, heat shock proteins, inflammatory mediators, immunomodulatory cytokines, and death receptors to enhance antitumor immune responses.

Figures

Figure 1
Figure 1
Confluence of SABR and Immunotherapy. Apoptosis can be initiated by SABR-induced DNA damage and upregulation of the p53 tumor suppressor gene. In addition, apoptosis can be triggered by SABR-induced damage to the cellular lipid membrane, which can induce ceramide formation and activate the SAPK/JNK signaling pathway. Thus, SAPK/JNK can upregulate PKR expression, which can induce MHC and cytokines via NF-κB. SABR can induce cellular expression of MHC Class I, adhesion molecules, costimulatory molecules, heat shock proteins, inflammatory mediators, immunomodulatory cytokines, and death receptors.

References

    1. Brenner DJ. The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction. Seminars in Radiation Oncology. 2008;18(4):234–239.
    1. Kirkpatrick JP, Meyer JJ, Marks LB. The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery. Seminars in Radiation Oncology. 2008;18(4):240–243.
    1. Leith JT, Cook S, Chougule P, et al. Intrinsic and extrinsic characteristics of human tumors relevant to radiosurgery: comparative cellular radiosensitivity and hypoxic percentages. Acta Neurochirurgica, Supplement. 1994;62:18–27.
    1. Guerrero M, Li XA. Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy. Physics in Medicine and Biology. 2004;49(20):4825–4835.
    1. Park C, Papiez L, Zhang S, Story M, Timmerman RD. Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy. International Journal of Radiation Oncology Biology Physics. 2008;70(3):847–852.
    1. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300(5622):1155–1159.
    1. Truman JP, García-Barros M, Kaag M, et al. Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery. PLoS One. 2010;5(8) Article ID e12310.
    1. Utermöhlen O, Karow U, Löhler J, Krönke M. Severe impairment in early host defense against Listeria monocytogenes in mice deficient in acid sphingomyelinase. Journal of Immunology. 2003;170(5):2621–2628.
    1. Chen FH, Chiang CS, Wang CC, et al. Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors. Clinical Cancer Research. 2009;15(5):1721–1729.
    1. Szeifert GT, Kondziolka D, Atteberry DS, et al. Radiosurgical pathology of brain tumors: metastases, schwannomas, meningiomas, astrocytomas, hemangioblastomas. Progress in neurological surgery. 2007;20:91–105.
    1. Wasserman J, Blomgren H, Rotstein S, Petrini B, Hammarstrom S. Immunosuppression in irradiated breast cancer patients: in vitro effect of cyclooxygenase inhibitors. Bulletin of the New York Academy of Medicine. 1989;65(1):36–44.
    1. North RJ. Radiation-induced, immunologically mediated regression of an established tumor as an example of successful therapeutic immunomanipulation. Preferential elimination of suppressor T cells allows sustained production of effector T cells. Journal of Experimental Medicine. 1986;164(5):1652–1666.
    1. Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clinical Cancer Research. 2005;11(2 I):728–734.
    1. Ohuchida K, Mizumoto K, Murakami M, et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Research. 2004;64(9):3215–3222.
    1. Merrick A, Errington F, Milward K, et al. Immunosuppressive effects of radiation on human dendritic cells: reduced IL-12 production on activation and impairment of naïve T-cell priming. British Journal of Cancer. 2005;92(8):1450–1458.
    1. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. Journal of Experimental Medicine. 2006;203(5):1259–1271.
    1. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–1964.
    1. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Medicine. 2007;13(9):1050–1059.
    1. Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Research. 2004;64(12):4328–4337.
    1. Finkelstein SE, Heimann DM, Klebanoff CA, et al. Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer. Journal of Leukocyte Biology. 2004;76(2):333–337.
    1. Liao YP, Wang CC, Schaue D, Iwamoto KS, McBride WH. Local irradiation of murine melanoma affects the development of tumour-specific immunity. Immunology. 2009;128(1):e797–e804.
    1. Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. Journal of Immunology. 2005;174(12):7516–7523.
    1. Stone HB, Peters LJ, Milas L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. Journal of the National Cancer Institute. 1979;63(5):1229–1235.
    1. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–595.
    1. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clinical Cancer Research. 2009;15(17):5379–5388.
    1. Schaue D, Comin-Anduix B, Ribas A, et al. T-cell responses to survivin in cancer patients undergoing radiation therapy. Clinical Cancer Research. 2008;14(15):p. 4883.
    1. Restifo NP, Antony PA, Finkelstein SE, et al. Assumptions of the tumor ‘escape’ hypothesis. Seminars in Cancer Biology. 2002;12(1):81–86.
    1. Friedman EJ. Immune modulation by ionizing radiation and its implications for cancer immunotherapy. Current Pharmaceutical Design. 2002;8(19):1765–1780.
    1. Overwijk WW, Theoret MR, Finkelstein SE, et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. Journal of Experimental Medicine. 2003;198(4):569–580.
    1. Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. Journal of Experimental Medicine. 2005;202(7):907–912.
    1. Chiang CS, McBride WH. Radiation enhances tumor necrosis factor α production by murine brain cells. Brain Research. 1991;566(1-2):265–269.
    1. Quarmby S, Kumar P, Kumar S. Radiation-induced normal tissue injury: role of adhesion molecules in leukocyte-endothelial cell interactions. International Journal of Cancer. 1999;82(3):385–395.
    1. Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Research. 2002;62(5):1462–1470.
    1. Nikitina E, Gabrilovich DI. Combination of γ-irradiation and dendritic cell administration induces a potent antitumor response in tumor-bearing mice: approach to treatment of advanced stage cancer. International Journal of Cancer. 2001;94(6):825–833.
    1. Ahn GO, Brown JM. Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: experimental models and clinical perspectives. Cell Cycle. 2009;8(7):970–976.
    1. Kachikwu EL, Iwamoto KS, Liao YP, et al. Radiation enhances regulatory T cell representation. International Journal of Radiation Oncology, Biology, Physics. In press.
    1. McBride WH, Chiang CS, Olson JL, et al. A sense of danger from radiation. Radiation Research. 2004;162(1):1–19.
    1. Yee C, Riddell SR, Greenberg PD. In vivo tracking of tumor-specific T cells. Current Opinion in Immunology. 2001;13(2):141–146.
    1. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunology. 2002;3(11):991–998.
    1. Howie S, McBride WH. Tumor-specific T helper activity can be abrogated by two distinct suppressor cell mechanisms. European Journal of Immunology. 1982;12(8):671–675.
    1. Spiotto MT, Fu YX, Schreiber H. Tumor immunity meets autoimmunity: antigen levels and dendritic cell maturation. Current Opinion in Immunology. 2003;15(6):725–730.
    1. Marks LB, Hall EJ, Brenner DJ. Extrapolating hypofractionated radiation schemes from radiosurgery data: regarding Hall et al, IJROBP 21:819–824; 1991 and Hall and Brenner, IJROBP 25:381–385; 1993. International Journal of Radiation Oncology Biology Physics. 1995;32(1):274–276.
    1. Wang JZ, Huang Z, Lo SS, Yuh WTC, Mayr NA. A generalized linear-quadratic model for radiosurgery, stereotactic body radiation therapy, and high-dose rate brachytherapy. Science Translational Medicine. 2010;2(39) Article ID 39ra48.
    1. Hadziahmetovic M, Loo BW, Timmerman RD, et al. Stereotactic body radiation therapy (stereotactic ablative radiotherapy) for stage I non-small cell lung cancer–updates of radiobiology, techniques, and clinical outcomes. Discovery medicine. 2010;9(48):411–417.
    1. Cho J, Kodym R, Seliounine S, Richardson JA, Solberg TD, Story MD. High dose-per-fraction irradiation of limited lung volumes using an image-guided, highly focused irradiator: simulating stereotactic body radiotherapy regimens in a small-animal model. International Journal of Radiation Oncology Biology Physics. 2010;77(3):895–902.
    1. Wong J, Armour E, Kazanzides P, et al. High-resolution, small animal radiation research platform with X-ray tomographic guidance capabilities. International Journal of Radiation Oncology Biology Physics. 2008;71(5):1591–1599.
    1. Finkelstein SE, Trotti A, Rao N, et al. The Florida Melanoma Trial I: a prospective multi-center phase I/II trial of post operative hypofractionated adjuvant radiotherapy with concurrent interferon-α-2b immunotherapy in the treatment of advanced stage III melanoma with long term toxicity follow up. ISRN Immunology. In press.
    1. Finkelstein SE, Iclozan C, Bui MM, et al. Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. International Journal of Radiation Oncology, Biology, Physics. In press.

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