Modulating T-cell Responses to Enhance the Effects of Radiotherapy

Radiotherapy has been a key component of cancer treatment for over a hundred years, with the understanding that its action was driven only by direct and indirect toxic effects on the tumor cells. With the advent of immunotherapy in recent decades, interest in radiotherapy has expanded beyond just its ability to kill malignant cells directly, to include the potential for augmenting the antitumor immune response in combination with immunotherapy. However, radiotherapy has also been clearly demonstrated to exert immunosuppressive effects, reported in both preclinical and clinical settings, and this means that it has a double-edged immune effect. The cytotoxic effects of T cells are a critical element of the antitumor immune response, and it is cytotoxic T lymphocytes (CTL) that have been the primary target of clinically mature immunotherapies to date, notably antibodies blocking negative regulation of T cells. In this context, the question is how the combination of radiotherapy and immunotherapy can be optimized to leverage the immune-promoting effects of radiotherapy, while minimizing its immune deleterious consequences. In this review, we present the most recent understanding of this promising therapeutic combination, with a specific focus on modulating T-cell responses, also highlighting the need for more in-depth investigation of the responsible underlying mechanisms of action.