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  • Review Article
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Assessing the interactions between radiotherapy and antitumour immunity

Nature Reviews Clinical Oncology volume 16, pages 729–745 (2019)Cite this article

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Abstract

Immunotherapy, specifically the introduction of immune checkpoint inhibitors, has transformed the treatment of cancer, enabling long-term tumour control even in individuals with advanced-stage disease. Unfortunately, only a small subset of patients show a response to currently available immunotherapies. Despite a growing consensus that combining immune checkpoint inhibitors with radiotherapy can increase response rates, this approach might be limited by the development of persistent radiation-induced immunosuppression. The ultimate goal of combining immunotherapy with radiotherapy is to induce a shift from an ineffective, pre-existing immune response to a long-lasting, therapy-induced immune response at all sites of disease. To achieve this goal and enable the adaptation and monitoring of individualized treatment approaches, assessment of the dynamic changes in the immune system at the patient level is essential. In this Review, we summarize the available clinical data, including forthcoming methods to assess the immune response to radiotherapy at the patient level, ranging from serum biomarkers to imaging techniques that enable investigation of immune cell dynamics in patients. Furthermore, we discuss modelling approaches that have been developed to predict the interaction of immunotherapy with radiotherapy, and highlight how they could be combined with biomarkers of antitumour immunity to optimize radiotherapy regimens and maximize their synergy with immunotherapy.

Key points

  • Peripheral absolute lymphocyte count is a high-level marker of systemic immune status and is correlated with survival after radiotherapy in multiple tumour types.

  • Investigation continues into additional markers of immune status, including circulating lymphocyte subsets, humoral markers, cytokines, and tumour-infiltrating lymphocytes; these markers tend to be highly indication-specific and context-specific.

  • A variety of imaging methods based on MRI, single-photon emission CT (SPECT), and PET enable imaging of both the current distributions and dynamics of immune cell populations.

  • Mathematical models of the tumour–immune interaction and the influence of radiotherapy on this system can be broadly classified as either systemic or regional-interacting models.

  • Both circulating markers and advanced imaging methods will be needed to refine these models based on clinical patient data.

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Fig. 1: Correlation of radiation-induced lymphopenia with survival.
Fig. 2: Integration of biomarker data with mathematical models.
Fig. 3: Effect of radiotherapy technique on immune response.

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Acknowledgements

The authors thank H. Paganetti, H. Willers, M. Cobbold, T. Hong and H. Shih at Massachusetts General Hospital for their clinical insights and helpful discussions.

Peer review information

Nature Reviews Clinical Oncology thanks B. Frey, J. Chang, K. Young and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Clemens Grassberger, Florence K. Keane & Jay S. Loeffler

  2. Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA

    Susannah G. Ellsworth

  3. Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA, USA

    Moses Q. Wilks

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C.G., S.G.E., M.Q.W., and F.K.K. researched data for the article. All authors made a substantial contribution to the discussion of content, wrote the manuscript, and reviewed and/or edited the manuscript before submission.

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Grassberger, C., Ellsworth, S.G., Wilks, M.Q. et al. Assessing the interactions between radiotherapy and antitumour immunity. Nat Rev Clin Oncol 16, 729–745 (2019). https://doi.org/10.1038/s41571-019-0238-9

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