| dc.description.abstract | The sympathetic nervous system (SNS) is an important regulator of immune cell function during homeostasis and states of inflammation. Recently, the SNS has been found to bolster tumor growth and impair the development of anti-tumor immunity. However, it is unclear whether the SNS can modulate antigen presenting cell (APC) function. In project 1, we investigated the effects of SNS signaling in monocyte-derived macrophages (moMФ) and dendritic cells (DCs) and further combined the nonspecific β-blocker propranolol with a peptide cancer vaccine for the treatment of melanoma in mice. We report the novel finding that norepinephrine treatment dramatically altered moMФ cytokine production and T cell priming, whereas DCs were unresponsive to norepinephrine and critically lack β2-adrenergic receptor expression. In addition, we show that propranolol plus cancer vaccine enhanced peripheral DC maturation, increased the intratumor proportion of effector CD8+ T cells, and decreased the presence of intratumor PD-L1+ myeloid-derived suppressor cells. Furthermore, this combination dramatically reduced tumor growth compared to vaccination alone. Taken together, these results offer novel insights into the cell-specific manner by which the SNS regulates the APC immune compartment and provide strong support for the use of propranolol in combination with cancer vaccines to improve patient response rates and survival.
Occluded limb arteries require immediate revascularization, but return of blood flow causes additional tissue damage through generation of reactive oxygen species (ROS) and dysregulation of nitric oxide (NO) production. In project 2, we report a hybrid molecule SA-10 with both NO donating and ROS scavenging abilities for the treatment of limb ischemia-reperfusion (I/R) diseases. SA-10 demonstrated potent cytoprotection and tube formation activity in endothelial cells under H2O2-induced oxidative stress. In addition, SA-10 loaded poly(lactic-co-glycolic acid) nanoparticles
(SA-10 NPs) were delivered intramuscularly in two murine hindlimb ischemia models. In the acute I/R model, SA-10NP significantly reduced muscle damage, hyper inflammation, and lung edema. In the chronic ischemia model, SA-10 significantly improved blood perfusion and physical endurance over 30 days. Elderly patients with acute and chronic limb ischemia have limited options for surgical or endovascular interventions, so a therapeutic alternative to surgery such as SA-10NP is greatly needed. | |
