Downregulation of A2ar by Sirna Loaded Peg-Chitosan-Lactate Nanoparticles Restores the T Cell Mediated Anti-Tumor Responses Through Blockage of Pka/Creb Signaling Pathway Publisher Pubmed



Masjedi A^{1, 2} ; Hassannia H³ ; Atyabi F⁴ ; Rastegari A⁴ ; Hojjatfarsangi M^{5, 6} ; Namdar A⁷ ; Soleimanpour H⁸ ; Azizi G⁹ ; Nikkhoo A¹ ; Ghalamfarsa G¹⁰ ; Mirshafiey A¹¹ ; Jadidiniaragh F^{12, 13} Show Affiliations
Source: International Journal of Biological Macromolecules Published:2019

Abstract

Adenosine and its receptors are novel promising targets for cancer immunotherapy. In here, we aimed to evaluate the efficacy of Polyethylene glycol (PEG)-chitosan-lactate (PCL) nanoparticles (NPs) loaded with A2AR-specific siRNA for interfering with differentiation and function of T cells derived from the 4T1 breast tumor-bearing Balb/C mice, ex vivo. The size of synthesized NPs was about 100 nm in association with low polydispersive index (pdi < 0.3) and a zeta potential of 11 mV. In association with good physicochemical characteristics, NPs exhibited high transfection efficiency in T cells and low toxicity on the various cell lines. T cells were treated with A2AR siRNA-loaded NPs demonstrated suppressed expression of A2AR which was associated with increased proliferation, reduced apoptosis, increased production of inflammatory and reduced secretion of inhibitory cytokines compared to untreated T cells. Moreover, differentiation of conventional T cells purified from tumor-bearing mice to regulatory T cells (Treg) was blocked using A2AR-specific siRNA-loaded NPs. These immune-stimulatory effects were in part through downregulation of protein kinase A/cAMP-response element binding protein (PKA/CREB) axis and upregulation of nuclear factor-κB (NF-κB). © 2019 Elsevier B.V.