Abstract
It is becoming clear that ionizing radiation positively influences certain immune parameters, which opens the possibility for combining radio- and immunotherapies in cancer treatment. The presence of functionally competent dendritic cells (DCs) is crucial in mounting a successful antitumor immune response. While it has been shown that DCs are relatively radioresistant, few and contradictory data are available on how ionizing radiation alters the functional integrity of these cells. Therefore, our objective was to investigate the effect of whole-body irradiation on the function of splenic DCs. C57Bl/6 mice were irradiated with 0.1, 0.25, and 2 Gy X-rays and changes in the phenotype of splenic DCs were compared to unirradiated controls. An increase was seen in DC surface markers influencing DC-T cell interactions. In vivo cytokine production was determined by direct intracellular cytokine staining. Irradiation with 2 Gy induced a 1.6-fold increase in IL-1α production, while the combination of irradiation and lipopolysaccharide (LPS) treatment induced a 3.9-fold increase, indicating a strong synergism between irradiation and LPS stimulation. Interaction of DCs with effector and regulatory T cells was investigated in a mixed lymphocyte reaction. While DCs from control animals induced stronger proliferation of regulatory T cells, DCs from animals irradiated with 2 Gy induced stronger proliferation of effector T cells. Antigen uptake and presentation was investigated by measuring the capacity of DCs to internalize and present ovalbumine (OVA)-derived peptides on their major histocompatibility complex (MHCI) molecules. Irradiation with 2 Gy did not influence antigen uptake or presentation, while low doses stimulated antigen uptake and reduced the level of antigen presentation. In conclusion, high-dose in vivo irradiation induced increased expression of T cell costimulatory markers, enhanced production of proinflammatory cytokines and a stronger stimulation of effector T cell proliferation than that of regulatory T cells. However, it did not influence DC antigen uptake or presentation. On the other hand, low-dose irradiation increased antigen uptake and lowered antigen presentation of DCs, indicating that low- and high-dose irradiation act on different pathways in DCs.
Highlights
Radiation was considered as a net immune-suppressing agent for decades [1]
These findings opened the gate for studies exploring optimal combinations of radiotherapy and immunotherapy in order to achieve a synergistic effect
We investigated radiation effects on the functional parameters of Tregs and proved that the Treg pool was much less affected after irradiation compared to other splenocyte subpopulations, the functional integrity of Tregs was still compromised after irradiation with 2 Gy [22]
Summary
Radiation was considered as a net immune-suppressing agent for decades [1]. While the exquisite radiosensitivity of the lymphoid system in terms of radiation-induced cell killing is out of the question, recent advances in radiobiology and immunology have made this picture more complex. Tumor cells release so-called danger signals in response to radiation, which, in turn, can lead to immune activation and induction of immunogenic cell death [3,4,5]. Irradiation can enhance the production of immune-stimulatory cytokines, and improve infiltration of tumors with lymphocytes. Most importantly, these immune-modulatory effects are restricted locally to the tumor site but manifest at a systemic level [6]. Several clinical observations have been published supporting the immune-stimulatory effect of radiation [7,8]. These findings opened the gate for studies exploring optimal combinations of radiotherapy and immunotherapy in order to achieve a synergistic effect
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