Abstract P3-01-02: B2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells

Abstract

Abstract Chronic stress is thought to suppress immunity; however, details about how chronic stress affects tumor growth and anti-tumor immune responses are still missing or poorly understood. Catecholamines (epinephrine, norepinephrine) released during sympathetic nerve stimulation 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 promoting tumor growth, differentiation and metastasis. Here, we demonstrate that the chronic adrenergic stress (as manipulated by a) housing temperature (which affects norepinephrine (NE) production, b) use of b-AR agonists or antagonists, or c) using β2-AR knockout mice regulates the accumulation and the pro-tumor phenotype of MDSCs. This same result was seen using two different murine models of breast cancer (4T1 and AT-3) and through the use of β2-AR knockout mice, we found that these effects are dependent on β2-adrenergic receptor (β2-AR) signaling. Using an agonist of β-AR signaling, we found that the activation of β2-AR signaling increases the expression of immunosuppressive molecules such as arginase-I and PDL-1 in MDSCs and enhances their immune-regulatory functions. β2-AR expression in MDSCs was induced by tumor promoting cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF). The survival of MDSCs is increased upon the activation of β2-AR on MDSCs in a Fas-FasL dependent manner. The regulation by β-AR signaling on MDSCs is dependent upon phosphorylation of STAT3 as a pivotal transcription factor in the function and expansion of MDSCs while MDSCs lacking β2-AR had poorer survival in both spleen and tumor. In murine tumor models, we found that the tumor promoting effects of β2-AR activation can be prevented by simple treatment of mice with β-blockers or by peripheral sympathectomy using 6-hydroxydopamine (6-OHDA). Furthermore, treatment with β-AR agonist increases the generation and immunosuppressive functions of MDSCs derived from human PBMCs in vitro. These data reveal a major, physiologically relevant role for nervous activity and adrenergic stress in MDSC-tumor biology and underscore the clinical potential for blockade of a previously unrecognized β2-AR-MDSC axis to improve immunotherapy. Keywords: β2 adrenergic receptor, MDSC, Chronic Stress, Tumor, STAT3 Citation Format: Hemn Mohammadpour, Cameron R. MacDonald, Guanxi Qiao, Minhui Chen, Bowen Dong, Bonnie L. Hylander, Philip L. McCarthy, Scott I. Abrams, Elizabeth A. Repasky. B2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-02.