The Suppression of Metastases and the Change in Host Immune Response after Low-Dose Total-Body Irradiation in Tumor-Bearing Rats

Abstract

We have shown that metastasis is suppressed by low-dose total-body irradiation (TBI) in tumor-bearing rats. We have evaluated the immunological effects of low-dose TBI. Total-body irradiation with 0.2 Gy was given 14 days after the implantation of 5 x 10(5) allogenic hepatoma cells (KDH-8) which produce transforming growth factor beta (TGF-beta). On day 21, the splenocytes and tumor-tissue infiltrating lymphocytes were analyzed by FACScan and RT-PCR for the mRNA of the genes that encode tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), TGF-beta, interleukin (IL)-4, IL-10 and IL-6. The same procedure was conducted with untreated rats and with rats that underwent local irradiation with 0.2 Gy. The low-dose TBI significantly decreased the incidence of lung and lymph node metastasis (P < 0.01), whereas the same dose of local irradiation had no effect on the incidence of metastasis. The proportion of CD8+ cells in splenocytes increased in the low-dose TBI group (P < 0.01) compared to the locally irradiated and the untreated groups. The tumor-tissue infiltrating lymphocytes were also significantly increased after low-dose TBI (P < 0.01). The FACScan analysis revealed that 72% of the tumor-tissue infiltrating lymphocytes were CD8+. In both spleen and tumor tissue after low-dose TBI, mRNA expression of the genes that encode IFN-gamma and TNF-alpha increased, while that of the Tgfb gene decreased. There was no expression of the mRNAs of the Il4, Il6 and Il10 genes. CD8+ cells and the cytokine network may play an important role in the antitumor effect of low-dose TBI.

The melatonin immunomodulatory actions in radiotherapy

“…Th1 cytokines are involved in inflammatory reactions including activation of macrophages and T cells, whereas Th2 cytokines stimulate humoral and allergic responses of the immune system. This imbalance between Th1 and Th2 cytokines production was involved in the long-term side effects in people who were exposed to radiation (Hashimoto et al 1999;Emerit et al 1995;Kusunoki et al 2010;Kusunoki and Hayashi 2008;Bower et al 2002Bower et al , 2009). …”

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

“…In one report, lowdose irradiation following transplantation of a hepatoma cell line in a rat model resulted in an increased proportion of CD8-positive splenocytes, increased numbers of tumor infiltrating lymphocytes, increased TNF-a and IFN-g expression and decreased TGF-b expression. This response correlated with a reduction in metastases (Hashimoto et al, 1999). Another study demonstrated an increased CD4:CD8 T cell ratio, and decreased expression of TGF-b and VEGF following low-dose total body-irradiation, which correlated with delayed tumor growth in mice transplanted with the Lewis lung carcinoma cell line (Miller et al, 2003).…”

“…A number of factors may explain why the consistent characterization of immune responses to radiation remains elusive including differences in radiosensitivity or reactivity of different cell and tissue types, and dose-dependent effects. The latter have been explored in a number of studies, some of which suggest that lower doses of radiation have a greater potential to enhance immune responses (Hashimoto et al, 1999;Cao et al, 2002;Ina and Sakai, 2005;Shigematsu et al, 2007).…”

A phase II trial of adjuvant low-dose total body irradiation in non-hodgkin's lymphoma patients following standard CHOP

“…The occurrence of this transient increase in liver enzymes cannot therefore be easily explained. Experimental data showed that LTBI can induce a degree of immune stimulation (17) in various animal models (18). Very few human data suggest that similar effects may be seen in humans (19).…”