title: The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications.
abstract: By inducing DNA damage, radiotherapy both reduces tumor burden and enhances anti-tumor immunity. Here, we will review the mechanisms by which radiation induces anti-tumor immune responses that can be augmented using immunotherapies to facilitate tumor regression. Radiotherapy increases inflammation in tumors by activating the NF-κB and the Type I interferon response pathways to induce expression of pro-inflammatory 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 non-malignant stroma that present cognate antigen. Yet, these anti-tumor 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 is demonstrating early clinical potential. Overall, this review will provide a global view for how radiation and the immune system converge to target cancers and the early attempts to exploit this synergy in clinical practice.
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL; Ludwig Center for Metastases Research, The University of Chicago, Chicago, IL.
authors.forename: Michael
authors.initials: M
authors.lastname: Spiotto
authors.affiliation: Department of Pathology, University of Texas - Southwestern, Dallas, TX.
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL; Ludwig Center for Metastases Research, The University of Chicago, Chicago, IL.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
keywords: Checkpoint blockade; Immunotherapy; Radiotherapy