Lymphopenia and intratumoral lymphocytic balance in the era of cancer immuno-radiotherapy

The immune response has been recognized as a major tumor-eradication component of radiotherapy. This review studies, under a clinical perspective, two contrasting effects of radiotherapy, namely immunosuppression and radiovaccination. We critically reviewed the available clinical and experimental experience on radiotherapy-induced lymphopenia. Radiation-induced tumor damage promotes radio-vaccination, enhances cytotoxic immune responses, and potentiates immunotherapy. Nevertheless, radiotherapy induces systemic and intratumoral lymphopenia. The above effects are directly related to radiotherapy fractionation and field size/location, and tumor characteristics. Hypofractionated stereotactic and accelerated irradiation better promotes radio-vaccination and produces less severe lymphopenia. Adopting cytoprotective policies and combining lympho-stimulatory agents or agents blocking regulatory lymphocyte activity are awaited to unmask the radio-vaccination effect, enhancing the efficacy immuno-radiotherapy. Radiation-induced lymphopenia and immunosuppression are important issues that should be considered in the design of immuno-radiotherapy clinical trials.