Harnessing the Immunomodulatory Effects of Radiation Therapy

In this article, we discuss the immunogenicity of radiation-induced cell death and describe the innate immune signaling pathways that precede adaptive antitumoral immunity. The innate and adaptive immune systems work in concert to generate systemic immune responses. In the setting of cancer, DNA damage caused by radiotherapy activates the innate immune system while tumor cell death liberates antigen that serves as a target for adaptive immunity. The immunomodulatory effects of radiation have been investigated in preclinical models; here we summarize the available data, with particular attention to the effects of radiotherapy timing, location, dose, and fractionation strategy on the antitumoral immune response. We synthesize preclinical and clinical information regarding the potential superiority of hypofractionated radiation for induction of proinflammatory responses. Although many questions remain, early successes with combining immunotherapy and radiotherapy merit further inquiry into the dose and fractionation strategies best able to activate and sustain an antitumoral response.