Abstract P4-04-01: β2-adrenergic receptor signaling regulates metabolic pathways critical for the function of myeloid-derived suppressor cells

Abstract

Abstract Summary Nerve-driven chronic adrenergic stress can suppress anti-tumor immunity. However, details are still missing or poorly understood. Catecholamines (epinephrine, norepinephrine) released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type including myeloid derived suppressor cells (MDSCs). MDSCs are increasingly recognized as critical players in tumor immunology because, in addition to their fundamental roles in suppressing effector NK cells, CD8+ T cells and CD4+ T cells, they also play a direct role in tumor growth, differentiation and metastasis. Recently, we have shown that β2 adrenergic receptor signaling activated by chronic stress increases the immunosuppressive function of MDSCs, but the precise mechanisms remain unresolved. Building upon our earlier work, we now have discovered that the beta-2 adrenergic receptor (β2-AR) stress pathway drives the immune suppressive activity of MDSCs through altering their metabolism. First, we found that the expression of surface β2-AR on MDSCs increases with tumor growth in 4T1 breast cancer model and patients with breast cancer. We also found that β2-AR signaling decreases glycolysis, while increasing oxidative phosphorylation and fatty acid oxidation (FAO). β2-AR signaling also increased mitochondrial intensity and mitochondrial potential of MDSCs both in vitro and in vivo. β2-AR signaling in MDSCs also increased the expression of Carnitine Palmitoyltransferase 1A (CPT1A) necessary for the FAO-mediated immunosuppressive function of MDSCs. Blocking CPT1A using etomoxir decreased tumor growth and immunosuppressive function of MDSCs in Wild Type (WT) mice but not β2-AR-/- mice or severe combined immunodeficient mice (SCID) mice. Moreover, we found that β2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2 in both mouse MDSCs and. PBMCs derived MDSCs. Together, our data reveal that stress-driven β2-AR signaling is an important physiological determinant that regulates key metabolic pathways in MDSCs enabling their immunosuppressive function. These data reveal a major, physiologically relevant role for nervous activity and adrenergic stress in MDSC-tumor biology. Keywords: β2 adrenergic receptor, stress, MDSC, Metabolism, Breast Cancer, Citation Format: Hemn Mohammadpour. β2-adrenergic receptor signaling regulates metabolic pathways critical for the function of myeloid-derived suppressor cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-01.