Blockade of Host β2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs

Abstract

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 CD4Foxp3 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.

The updated landscape of tumor microenvironment and drug repurposing

“… 27 , 145 , 146 High levels of norepinephrine suppress DC development and recruit MDSC to TME, causing tumor progression. 147 The sympathetic nervous system guides the recruitment of macrophages or NK cells to tumor via β-adrenergic signaling. 148 Elevated intratumoral IL-6 levels are seen in excised samples of stressed ovarian cancer patients compared with control patients.…”

β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells

“…For example, β2-AR activation in T cells was seen to suppress their ability to secrete interferon-γ (IFN-γ) in response to infection with vesicular stomatitis virus (23) and impair metabolic reprogramming during T cell activation (11). High levels of NE also impair dendritic cell (DC) maturation (24,25) and increase MDSC recruitment into the tumor microenvironment (TME) (26). Murine studies from our lab showed that chronic β2-AR signaling suppresses antitumor CD8 + T cell function and increases populations of MDSCs and Tregs in the spleen and tumor microenvironment, respectively (27,28).…”

Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation

“…That this has a direct impact on the outcomes of studies involving a variety of disease models, including studies involving immune responses has been shown by comparing outcomes in mice housed under standard vs. thermoneutral temperatures [24][25][26][27] . Furthermore, our lab discovered that this chronic stress suppresses baseline anti-tumor immunity and accelerates tumor growth and metastasis 28,29 , while it also suppresses graft versus host disease following allogeneic hematopoietic stem cell transplantation 30,31 . When tumor-bearing mice are housed at their thermoneutral temperature (~30°C), chronic adrenergic stress and norepinephrine production are significantly lowered, CD8 + T cell-dependent responses are significantly improved, while numbers and activities of immunosuppressive cells are reduced 29,32,33 .…”