Investigating the immune modulating effects of low dose ionizing radiation as a potential cancer therapy

Abstract

Ionizing radiation is an established treatment modality for cancer. Unlike targeted high dose therapies, there is growing evidence that low dose radiation (LDR) can promote tumor reduction indirectly via stimulation of the immune system. Natural killer (NK) cells are one of the main immune cells that have been implicated in LDR induced anticancer effects. Despite this, the exact cellular and molecular mechanisms responsible for the modulation of the immune system following LDR, including the stimulation of NK cells and their cytotoxic properties, have not yet been identified. The goals of this study were twofold; to elucidate the cellular mechanisms involved in LDR immune stimulation and to investigate the dose response for NK cell cytotoxicity. Initially, a small animal model was used to comprehensively characterize the dose dependent effects on various immune cells. Mice were exposed to whole-body x-ray doses of 0.1, 0.25, 0.5 and 3 Gy and were sacrificed two days post-irradiation for isolation of their spleen, lymph nodes and blood. Flow cytometry was then used for immunophenotyping to identify potential shifts in the relative abundance of major immune cell populations. Data from this cohort of mice suggested that 2 days following an acute single exposure, LDR caused no significant changes in the numbers of the immune cell types tested, and that high dose radiation (HDR) caused a decrease in the cell populations of these cells in the irradiated mice. To further investigate the impact of LDR on the NK cells in-vitro, the NK-92 cell line was used. NK-92 cells were exposed to x-ray doses ranging from 0.1 to 1 Gy, and cell growth rates were measured postradiation. NK cell cytotoxicity was then quantified through the co-culturing of NK-92 cells with the tumorigenic K-562 cells, and the percent cytotoxicity was measured using flow cytometry. Lastly, transcriptional analysis was performed on the main genes involved in regulating NK cytolytic activity. Overall, data showed that LDR did not cause any significant increase in the growth, cytotoxicity and gene expression of NK-92 cells. To conclude, although no evidence of immune stimulation was found following LDR in both the mice model and NK-92 cell line, this study was successful in providing a good characterization of the baseline immune response to lower doses of radiation in healthy models.