Abstract
Immuno-radiobiology is an interdisciplinary field exploring the interactions between ionizing radiation therapy, the tumor-immune microenvironment, and the immune system. The immune response to radiation is an important contributor to the efficacy of radiation therapy and has the potential to influence susceptibility to immunotherapies. Preclinical and some clinical evidence suggest combinations of radiation therapy with immunotherapies improve tumor response, but a greater understanding of their interacting mechanisms is needed to optimize these combinations. Multiple features of radiation therapy, including radiation dose, dose rate, dose heterogeneity, fractionation, and linear energy transfer (LET), influence the immunologic effects of radiation therapy. In this review, we evaluate how radiation therapy shapes antitumor immunity, focusing on both local immunogenicity and systemic immune modulation. Key mechanisms discussed include radiation-induced changes to both tumor cells and stroma that alter tumor immunogenicity. Tumor-intrinsic mechanisms of radiation response include nucleotide-sensing pathways, upregulation of tumor antigen presentation, and induced expression of death receptors and immune checkpoint ligands. Within the tumor microenvironment, we outline critical effects on immuno-radiobiology of immune-cell trafficking and activation, both directly and through effects on stromal cells, extracellular matrix, and the induction of immunogenic tumor cell death. Finally, we highlight the interplay with systemic immunity, often mediated through tumor-draining lymphatics, of localized radiation effects. Discussion of the effects of low- and heterogeneous-dose radiation demonstrates an increasing understanding of the varied effects that can be achieved by manipulating dosing and other physical properties of radiation therapy when combined with immunotherapy. We identify critical knowledge gaps and propose methodological approaches to overcoming clinical challenges.