The effect of ionizing radiation on regulatory T cells in health and disease.

Treg cells are key elements of the immune system which are responsible for the immune suppressive phenotype of cancer patients. Interaction of Treg cells with conventional anticancer therapies might fundamentally influence cancer therapy response rates. Radiotherapy, apart from its direct tumor cell killing potential, has a contradictory effect on the antitumor immune response: it augments certain immune parameters, while it depresses others. Treg cells are intrinsically radioresistant due to reduced apoptosis and increased proliferation, which leads to their systemic and/or intratumoral enrichment. While physiologically Treg suppression is not enhanced by irradiation, this is not the case in a tumorous environment, where Tregs acquire a highly suppressive phenotype, which is further increased by radiotherapy. This is the reason why the interest for combined radiotherapy and immunotherapy approaches focusing on the abrogation of Treg suppression has increased in cancer therapy in the last few years. Here we summarize the basic mechanisms of Treg radiation response both in healthy and cancerous environments and discuss Treg-targeted pre-clinical and clinical immunotherapy approaches used in combination with radiotherapy. Finally, the discrepant findings regarding the predictive value of Tregs in therapy response are also reviewed.