Blockade of Host {beta}2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs [TRANSPLANTATION]

Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that β2-adrenergic receptor (β2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a β2AR blocker significantly increases the GVT effect of donor CD8⁺ T cells by decreasing tumor burden without increasing graft-versus-host disease. β2AR-deficient host mice have significantly increased effector memory and central memory CD8⁺ T cells and improved reconstitution of T cells, including CD4⁺Foxp3⁺ regulatory T cells. Notably, β2AR deficiency induces increased CD11c⁺ DC development. Also, β2AR-deficient bone marrow–derived DCs induce higher CD8⁺ T cell proliferation and improved tumor killing in vitro. Metabolic profiling shows that β2AR deficiency renders DCs more immunogenic through upregulation of mTOR activity and reduction of STAT3 phosphorylation. Altogether, these findings demonstrate an important role for host β2AR signaling in suppressing T cell reconstitution and GVT activity.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2FLEaxX