RESUMEN
Myeloid-derived suppressor cells (MDSCs) are immunosuppressive myeloid cells found in patients with cancer and in mouse tumor models. They suppress anti-tumor immunity, resulting in the promotion of tumor growth. The relationship between nutrition and cancer has recently been reported by several research groups. Tumor cells rely on glutaminolysis, in which glutamine is metabolized into glutamate for energy production, and hence, glutamate levels are elevated in tumor-bearing hosts. However, the mechanism of regulation of tumor progression by glutamate still remains unclear. In this study, we found that the metabotropic glutamate receptor (mGluR) 2/3 was expressed on MDSCs, and an mGluR2/3 antagonist LY341495 attenuated the immunosuppressive activity of MDSCs. Furthermore, we observed that LY341495 treatment inhibited B16-F10 melanoma growth in vivo. Taken together, our data suggest that glutamate signaling promotes tumor growth by increasing the potency of immune suppression.
Asunto(s)
Aminoácidos/farmacología , Melanoma Experimental/tratamiento farmacológico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Xantenos/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/metabolismoRESUMEN
Oncolytic reovirus, which possesses 10 segments of dsRNA genome, mediates antitumor effects via not only virus replication in a tumor cell-specific manner, but also activation of antitumor immunity; however, the mechanism(s) of reovirus-induced activation of antitumor immunity have not been fully elucidated. Recent studies have demonstrated that overcoming an immunosuppressive environment in tumor-bearing hosts is important to achieve efficient activation of antitumor immunity. Among the various types of cells involved in immunosuppression, it has been revealed that myeloid-derived suppressor cells (MDSCs) are significantly increased in tumor-bearing hosts and play crucial roles in the immunosuppression in tumor-bearing hosts. In this study, we examined whether reovirus inhibits the immunosuppressive activity of MDSCs, resulting in efficient activation of immune cells after in vivo administration. The results showed that splenic MDSCs recovered from PBS-treated tumor-bearing mice significantly suppressed the Ag-specific proliferation of CD8+ T cells. In contrast, the suppressive activity of MDSCs on T cell proliferation was significantly reduced after reovirus administration. Reovirus also inhibited the immunosuppressive activity of MDSCs in IFN-ß promoter stimulator-1 knockout (KO) mice and in wild-type mice. In contrast, the immunosuppressive activity of MDSCs in TLR-3 KO mice was not significantly altered by reovirus treatment. The activation levels of CD4+ and CD8+ T cells were significantly lower in TLR3 KO mice than in wild-type mice after reovirus administration. These results indicate that reovirus inhibits the immunosuppressive activity of MDSCs in a TLR3, but not IFN-ß promoter stimulator-1, signaling-dependent manner.
Asunto(s)
Células Supresoras de Origen Mieloide/inmunología , Neoplasias Experimentales/inmunología , Infecciones por Reoviridae/inmunología , Receptor Toll-Like 3/inmunología , Escape del Tumor/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Virus Oncolíticos/inmunologíaRESUMEN
Disabled elderly individuals with kyphosis or loss of muscle strength often display forward head posture (FHP). This study aimed to determine the utility of a wheelchair incorporating pelvic support in preventing FHP in disabled elderly individuals. In this study, 14 disabled elderly individuals (87.1 ± 8.1 years) were selected. A wheelchair incorporating pelvic support (RX_ABS Lo) and a basic wheelchair (RX-1) were used. Each individual sat on both wheelchairs for 30 minutes. RX_ABS Lo has two belts to support the pelvic and thorax. Postures were recorded in the sagittal plane using a video camera. Cervical and trunk angles from horizontal were measured every 5 minutes. Simultaneously, contact areas and total pressures applied to the wheelchair seats and back supports were measured every 5 minutes. Comparisons of area under the curve values between the wheelchairs were performed using the paired t-test. Comparisons of time-dependent parameters for each wheelchair were performed using repeated one-way ANOVA. Cervical angles were greater when using RX_ABS Lo than RX-1. Although cervical angles were unchanged during 30 minutes when using RX_ABS Lo, the angles were significantly decreased after 30 minutes of using RX-1. Back support pressures and contact areas were greater for RX_ABS Lo than for RX-1. No significant difference in back support pressure distributions was observed during 30 minutes in the wheelchairs. The RX_ABS Lo may have utility in improving FHP by increasing cervical angles and improving stability with a back support to the upper thorax, lower thorax, and pelvis during prolonged sitting.