Immune modulation by hypofractionated stereotactic radiation therapy: Therapeutic implications

Stereotactic body radiation therapy (SBRT) has become an attractive treatment modality and a safe, non-invasive alternative to surgery to control primary or secondary malignant tumors. While emphasis has been on the local tumor control as a treatment objective for SBRT, the rare but intriguing observations of abscopal (or out-of-field) effects have pointed to the exciting possibility of activating anti-tumor immunity by using high-dose radiation. This review summarizes the available evidence supporting immune modulation by SBRT alone, as well as its potential combination with immunotherapy. Promising preclinical research has revealed an array of immune changes following SBRT, which could affect the balance between anti-tumor immunity and tumor-promoting immunosuppression. However, shifting this balance in the clinical setting to obtain survival benefits has rarely been achieved so far, emphasizing the need for a better understanding of the interactions between high-dose radiotherapy and immunity or immunotherapy. Nevertheless, the combination of SBRT with immunotherapy, particularly with immune checkpoint blockers, has the clear potential to substantially increase the rate of abscopal effects. This warrants further research in this area, both in mechanistic preclinical studies and in clinical trials incorporating correlative studies.