Immune Modulation by Ionizing Radiation and its Implications for Cancer Immunotherapy

Eric   J.   Friedman

Abstract

Ionizing radiation exhibits immunomodulatory properties, which could portend a future collaboration of cancer immunotherapy with radiation therapy. The “danger” model of immunity describes antigen-specific cellular immunity engendered by an inflammatory milieu. Dendritic cells (DCs) are attracted to this microenvironment, undergoing maturation after internalizing apoptotic and necrotic cellular debris. Mature DCs mediate antigen-specific cellular immunity via presentation of processed antigen to T cells. Administration of radiation has been utilized in vitro and in vivo to create an inflammatory setting, via induction of apoptosis, necrosis, cell surface molecules, and secretory molecules. Caspase-mediated cellular apoptosis is induced by radiation thro ugh multiple signaling pathways. Radiation upregulates expression of immunomodulatory surface molecules (MHC, costimulatory molecules, adhesion molecules, death receptors, heat shock proteins) and secretory molecules (cytokines, inflammatory mediators) in tumor, stromal, and vascular endothelial cells. Results of animal studies indicate possible radiation-mediated modulation of tumor antigen-specific immunity. Experimental data could indicate that the radiation-induced “danger” microenvironment engenders a DC-mediated antigen-specific immune response. Further enhancement of radiation-mediated inflammation and cell death can be achieved via administration of radiosensitizing pharmaceuticals. Radiation-mediated immune modulation currently remains unquantified and poorly understood. A major research effort will be required to elucidate mechanisms of action. With a thorough understanding of this phenomenon, we believe that ionizing radiation could be optimized for use with cancer vaccines and generate tumor antigen-specific cellular immunity.

Keywords: immune modulation, cancer immunotherapy, antigen-specific cellular immunity, multiple signaling pathways, cancer vaccines, innate and adaptive immunity, antigen processing, cross-presentation pathways, apoptotic pathways, radiation sensitizing agents