The intersection of radiotherapy and immunotherapy: Mechanisms and clinical implications

By inducing DNA damage, radiotherapy both reduces tumor burden and enhances antitumor immunity. Here, we review the mechanisms by which radiation induces antitumor immune responses, which can be augmented using immunotherapies to facilitate tumor regression. Radiotherapy increases inflammation in tumors by activating the nuclear factor kappa B and the type I interferon response pathways to induce expression of proinflammatory cytokines. This inflammation coupled with antigen release from irradiated cells facilitates dendritic cell maturation and cross-presentation of tumor antigens to prime tumor-specific T cell responses. Radiation also sensitizes tumors to these T cell responses by enhancing T cell infiltration into tumors and the recognition of both malignant cancer cells and nonmalignant stroma that present cognate antigen. Yet, these antitumor immune responses may be blunted by several mechanisms, including regulatory T cells and checkpoint molecules that promote T cell tolerance and exhaustion. Consequently, the combination of immunotherapy using vaccines and/or checkpoint inhibitors with radiation demonstrates early clinical potential. Overall, this Review will provide a global view on how radiation and the immune system converge to target cancers and the early attempts to exploit this synergy in clinical practice.