T-Cell Repertoire in Tumor Radiation: The Emerging Frontier as a Radiotherapy Biomarker

SIMPLE SUMMARY: Radiotherapy constitutes an essential component of the treatment for malignant disease. Besides its direct effect on cancer cells, namely, DNA damage and cell death, ionizing irradiation also mediates indirect antitumor effects that are mostly mediated by the immune system. Investigations into the processes underlying the interaction between radiotherapy and the immune system have uncovered mechanisms that can be exploited to promote the antitumor efficacy of radiotherapy both locally in the irradiated primary tumor and also at distant lesions in non-irradiated tumors. Because of its capacity to stimulate antitumor immunity, radiotherapy is also applied in combination with immune-checkpoint-inhibition-based immunotherapy. This review discusses the important pathways that govern the synergistic interactions between ionizing radiation and antitumor immune reactivity. Unravelling these involved mechanisms is mandatory for the successful application of anticancer radiotherapy and immunotherapy. We also place emphasis on the need for biomarkers that will aid in the selection of patients most likely to benefit from such combined treatments. ABSTRACT: Radiotherapy (RT) is a therapeutic modality that aims to eliminate malignant cells through the induction of DNA damage in the irradiated tumor site. In addition to its cytotoxic properties, RT also induces mechanisms that result in the promotion of antitumor immunity both locally within the irradiation field but also at distant tumor lesions, a phenomenon that is known as the “abscopal” effect. Because the immune system is capable of sensing the effects of RT, several treatment protocols have been assessing the synergistic role of radiotherapy combined with immunotherapy, collectively referred to as radioimmunotherapy. Herein, we discuss mechanistic insights underlying RT-based immunomodulation, which also enhance our understanding of how RT regulates antitumor T-cell-mediated immunity. Such knowledge is essential for the discovery of predictive biomarkers and for the improvement of clinical trials investigating the efficacy of radio-immunotherapeutic modalities in cancer patients.