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      Radiation effects on antitumor immune responses: current perspectives and challenges

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          Abstract

          Radiotherapy (RT) is currently used in more than 50% of cancer patients during the course of their disease in the curative, adjuvant or palliative setting. RT achieves good local control of tumor growth, conferring DNA damage and impacting tumor vasculature and the immune system. Formerly regarded as a merely immunosuppressive treatment, pre- and clinical observations indicate that the therapeutic effect of RT is partially immune mediated. In some instances, RT synergizes with immunotherapy (IT), through different mechanisms promoting an effective antitumor immune response. Cell death induced by RT is thought to be immunogenic and results in modulation of lymphocyte effector function in the tumor microenvironment promoting local control. Moreover, a systemic immune response can be elicited or modulated to exert effects outside the irradiation field (so called abscopal effects). In this review, we discuss the body of evidence related to RT and its immunogenic potential for the future design of novel combination therapies.

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          Combining radiotherapy and cancer immunotherapy: a paradigm shift.

          The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.
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            Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer.

            Ionizing radiation therapy (RT) is an important component in the management of breast cancer. Although the primary tumor can be successfully treated by surgery and RT, metastatic breast cancer remains a therapeutic challenge. Here we tested the hypothesis that the combination of RT to the primary tumor with CTLA-4 blockade can elicit antitumor immunity inhibiting the metastases. The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were injected s.c. with 4T1 cells, and treatment was started 13 days later when the primary tumors measured 5 mm in average diameter. Mice were randomly assigned to four treatment groups receiving: (1) control IgG (IgG), (2) RT + IgG, (3) 9H10 monoclonal antibody against CTLA-4, (4) RT + 9H10. RT was delivered to the primary tumor by one or two fractions of 12 Gy. 9H10 and IgG were given i.p. thrice after RT. Consistent with the fact that 4T1 is poorly immunogenic, 9H10 alone did not have any effect on primary tumor growth or survival. RT was able to delay the growth of the primary irradiated tumor, but in the absence of 9H10 survival was similar to that of control mice. In contrast, mice treated with RT + 9H10 had a statistically significant survival advantage. The increased survival correlated with inhibition of lung metastases formation and required CD8+ but not CD4+ T cells. The combination of local RT with CTLA-4 blockade is a promising new immunotherapeutic strategy against poorly immunogenic metastatic cancers.
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              Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer

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                Author and article information

                Contributors
                Journal
                Ther Adv Med Oncol
                Ther Adv Med Oncol
                TAM
                sptam
                Therapeutic Advances in Medical Oncology
                SAGE Publications (Sage UK: London, England )
                1758-8340
                1758-8359
                18 January 2018
                2018
                : 10
                : 1758834017742575
                Affiliations
                [1-1758834017742575]Innate Immunity Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [2-1758834017742575]Department of Oncology Clínica Universidad de Navarra, Pamplona, Spain
                [3-1758834017742575]German Cancer Research Center (DKFZ), Research Group Innate Immunity, Heidelberg, Germany
                [4-1758834017742575]Division of Oncology, Centre for Applied Biomedical Research (CIMA), Pamplona, SpainIdiSNA, Navarra Institute for Health Research, Pamplona, SpainDepartment of Biochemistry and Genetics, University of Navarra, Pamplona, Spain Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
                [5-1758834017742575]Programme in Immunotherapy, Centre for Applied Biomedical Research (CIMA), Pamplona, SpainDepartment of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
                [6-1758834017742575]Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), IdiSNA, Navarra Institute for Health Research, Department of Histology and Pathology, University of Navarra, School of Medicine, Pamplona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
                Author notes
                [#]

                These authors share authorship.

                Author information
                https://orcid.org/0000-0002-7289-2293
                Article
                10.1177_1758834017742575
                10.1177/1758834017742575
                5784573
                29383033
                c4d6ae4d-7de3-4eaf-bd31-3a5b6d8d8452
                © The Author(s), 2018

                This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 26 July 2017
                : 24 October 2017
                Categories
                Review
                Custom metadata
                January-December 2018

                abscopal,brachytherapy,checkpoint inhibitors,immunogenic cell death,immunotherapy,pd-1,radiotherapy

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