Immune Priming of the Tumor Microenvironment by Radiation

Although cancer immunotherapies such as immune checkpoint inhibitors have provided significant clinical benefits for some patients with advanced-stage disease, response rates remain low. Finding new treatment modalities that can synergize with immune checkpoint inhibitors to enhance antitumor immune responses without increasing systemic toxicity is an active area of research. Although most cancer immunotherapy research has focused on T cells and adaptive immunity, interest is growing in exploring the role of the innate immune response in promoting antitumor effects. Given radiation's effect on cancer cells, stromal cells, and the tumor microenvironment, radiation may be a powerful tool to modulate local immunological properties of the tumor and to promote systemic antitumor responses in combination with immunotherapeutic agents. Ionizing irradiation can induce a multitude of alterations within the tumor microenvironment. Unlike targeted therapies, radiation delivered to the tumor bed can prompt phenotypic changes in both normal stromal and cancer cells, leading to molecular and physiological alterations within the tumor microenvironment. These environmental modulations directly influence the degree of immunogenicity of the tumor microenvironment and may ultimately affect tumor responsiveness to cancer immunotherapies. Here we review the preclinical evidence for tumor microenvironment-mediated immune suppression and how radiation can modulate immune properties within a tumor. We then discuss the therapeutic opportunities for combining radiation with molecular agents to enhance tumor immunogenicity and how this represents a potential exciting strategy to complement immunotherapies including immune checkpoint blockers in cancer treatment. Ionizing irradiation can induce a multitude of alterations within the tumor microenvironment. Unlike targeted therapies, radiation delivered to the tumor bed can prompt phenotypic changes in both normal stromal and cancer cells, leading to molecular and physiological alterations within the tumor microenvironment. These environmental modulations directly influence the degree of immunogenicity of the tumor microenvironment and may ultimately affect tumor responsiveness to cancer immunotherapies. Here we review the preclinical evidence for tumor microenvironment-mediated immune suppression and how radiation can modulate immune properties within a tumor. We then discuss the therapeutic opportunities for combining radiation with molecular agents to enhance tumor immunogenicity and how this represents a potential exciting strategy to complement immunotherapies including immune checkpoint blockers in cancer treatment. short sequences of peptides produced from digested proteins that are presented on the cell surface by MHCs. a calcium-binding chaperone with key functions in the immune response including facilitating the folding of MHC class I molecules and their assembly factor tapasin, promotion of cellular phagocytic uptake, and activation of ICD. also known as integrin-associated protein (IAP); is a transmembrane protein that is overexpressed by several human cancers to inhibit clearance by phagocytes. a specific form of cell apoptosis capable of activating an adaptive immune response; can be induced by cytotoxic agents as well as radiotherapy or photodynamic therapy. the pressure exerted by the free interstitial fluid, which helps to determine transcapillary flow. IFP is often elevated in tumors. a set of cell-surface proteins that helps the immune system to recognize foreign pathogens in higher vertebrates. In humans the complex is also called the human leukocyte antigen (HLA) system. a heterogeneous cell population of myeloid lineage with the capacity to suppress both innate and adaptive immune responses mediated by NK, CD4+, and CD8+ T cells. new peptide synthesized from acquired mutations within the cancer genome that are recognized by body's immune system. membrane receptor found on T lymphocytes that recognizes MHC–antigen complex. a regulated cell-death process that promotes immune tolerance.