A Sense of Danger from Radiation¹

Abstract

Tissue damage caused by exposure to pathogens, chemicals and physical agents such as ionizing radiation triggers production of generic "danger" signals that mobilize the innate and acquired immune system to deal with the intrusion and effect tissue repair with the goal of maintaining the integrity of the tissue and the body. Ionizing radiation appears to do the same, but less is known about the role of "danger" signals in tissue responses to this agent. This review deals with the nature of putative "danger" signals that may be generated by exposure to ionizing radiation and their significance. There are a number of potential consequences of "danger" signaling in response to radiation exposure. "Danger" signals could mediate the pathogenesis of, or recovery from, radiation damage. They could alter intrinsic cellular radiosensitivity or initiate radioadaptive responses to subsequent exposure. They may spread outside the locally damaged site and mediate bystander or "out-of-field" radiation effects. Finally, an important aspect of classical "danger" signals is that they link initial nonspecific immune responses in a pathological site to the development of specific adaptive immunity. Interestingly, in the case of radiation, there is little evidence that "danger" signals efficiently translate radiation-induced tumor cell death into the generation of tumor-specific immunity or normal tissue damage into autoimmunity. The suggestion is that radiation-induced "danger" signals may be inadequate in this respect or that radiation interferes with the generation of specific immunity. There are many issues that need to be resolved regarding "danger" signaling after exposure to ionizing radiation. Evidence of their importance is, in some areas, scant, but the issues are worthy of consideration, if for no other reason than that manipulation of these pathways has the potential to improve the therapeutic benefit of radiation therapy. This article focuses on how normal tissues and tumors sense and respond to danger from ionizing radiation, on the nature of the signals that are sent, and on the impact on the eventual consequences of exposure.

Tetracycline-regulated intratumoral expression of interleukin-3 enhances the efficacy of radiation therapy for murine prostate cancer

“…For example, RT alone was recently shown to be able to stimulate intratumoral lymphocytes responsive to both a foreign model Ag and an endogenous tumor Ag in an OVAexpressing B16 melanoma tumor model. 3 However, while RT seems able to generate 'danger' signals in general there is little to suggest that these are potent 9 for the development of specific adaptive immunity. Immune stimulation may be additionally required and a recent randomized phase II clinical trial study.…”

“…3 The attraction of RT combined with IT is increased by findings that irradiation can modulate expression of several classes of genes in both murine and human cancers, 4 such as Fas, MHC-1, ICAM-1, and MUC-1, that might enhance their ability to serve as immune targets. 2,[5][6][7] On the other hand, while there is evidence that RT generates 'danger' signals that might mature dendritic cells (DCs) to present tumor antigen 8,9 there is no good evidence that this occurs in the clinic and such signals may be too weak to be effective. In a recent randomized phase II clinical trial study, 10 addition of recombinant vaccine administration to standard RT in patients with clinically localized prostate cancer showed that vaccination was safe and the generation of a PSAspecific cellular immune response was enhanced following RT.…”

Radiation therapy and Toll-like receptor signaling: implications for the treatment of cancer

“…Lymphocyte radiosensitivity is well established and remains the dominant explanation for this effect. However, substantial evidence suggests more varied effects of radiation on the immune system, prompting the re-characterization of radiation as 'immunomodulatory' rather than immunosuppressive (McBride et al, 2004). Increased expression of proinflammatory cytokines, including TNF-a and IL-1b following radiation has been reported (Hallahan et al, 1989;Ishihara et al, 1995;Nemoto et al, 1995;Hong et al, 1999).…”

“…Increased expression of proinflammatory cytokines, including TNF-a and IL-1b following radiation has been reported (Hallahan et al, 1989;Ishihara et al, 1995;Nemoto et al, 1995;Hong et al, 1999). These observations suggest a potential role for radiation in signaling 'danger' and, perhaps, in the activation of antigen presenting cells (McBride et al, 2004). Notwithstanding this, studies aimed at determining the effects of radiation on antigen-presenting cell phenotype, cytokine expression and function have been somewhat contradictory.…”

Lack of Association of Three Common Polymorphisms in Toll-like receptors (TLRs), TLR2+597T>C, +1350C>T and Arg753Gln with Cancer Risk: a Meta-analysis

“…TLRs are in serving as detectors of infectious diseases and cancer by activating dendritic cells (DCs) and other antigen-presenting cells to secrete proinflammatory cytokines and promoting DCs maturation to induct adaptive immune responses (Wang et al, 2008;Kumar et al, 2009). Ionizing radiation triggers production of generic "danger" signals may also activate effectors of innate immunity through TLR dependent mechanisms, and evoke the immune response to cancer (McBride et al, 2004;Roses et al, 2008). More than ten members (TLR1-10) of the TLR family have been reported (Rock et al, 1998;Du X et al, 2000;ChuangandUlevitch,2001).…”