Interactions between radiotherapy and immunotherapy

Background. Radiotherapy (RT) acts not only locally on cells but is also capable of inducing systemic reactions. What are the immunological foundations for radiation-induced systemic reactions and how can this knowledge be exploited for the design of multimodal radioimmunotherapy? Ionizing radiation can induce many forms of tumor cell death via DNA damage responses, which have different influences on the immune system. Immunogenic cancer cell death (ICD) is mainly characterized by the release of immune-activating danger signals. Particularly RT with higher single doses induces ICD and thereby triggers anti-tumor immune responses. Lower doses of ionizing radiation foster immune cell infiltration into the tumor; however, RT also ameliorates inflammation and has immune suppressive properties in that the release of transforming growth factor beta (TGF-beta) is increased after RT and immune checkpoint molecules, such as PD-L1 are upregulated. This calls for additional immunotherapies to exploit the properties of RT to act as an in situ vaccine and to subsequently induce local and systemic, abscopal, anti-tumor immune reactions. For the development of efficient radioimmunotherapies, a timely well-reasoned combination of the individual therapies based on knowledge of the immune-modulating modes of action of ionizing radiation has to be worked out. It might be inevitable in the future to develop radiation concepts with differing single doses in one therapy setting to exploit the maximum anti-tumor effect of the immune system.