β-adrenergic signaling modulates the development and activity of erythroid suppressor cells

Abstract

Abstract The neuroimmune response to stress has been linked to enhanced tumor proliferation, angiogenesis, and metastasis. In particular, signaling through β-adrenergic receptors has been demonstrated to promote a highly immunosuppressive tumor microenvironment by favoring the development and recruitment of suppressive immune cells, including regulatory T cells and myeloid-derived suppressive cells, that inhibit the cytotoxic CD8+ T cell response and enhance tumor progression. Interestingly, the complexity and scope of cancer immunosuppression extends beyond classical immune cells. Immunosuppressive erythroid progenitors, deemed erythroid suppressor cells (ESCs), have been shown to be prominent players in suppressing CD8+ T cell-mediated tumor responses; however, little is known about how these cells develop and are regulated. Thus, we examined if β-adrenergic signaling affects the development of ESCs and their role in tumor immunity. In this study, we show that β-adrenergic signaling promotes the accumulation of CD71+ Ter119+ erythroid progenitors consistent with the phenotypic description of ESCs in tumor-bearing mice. In characterizing the phenotype of these cells by flow cytometry and single-cell RNA sequencing, we elucidate unique features that endow these cells with immunosuppressive activity and illustrate their sensitivity to regulation by the sympathetic nervous system. We further demonstrate these erythroid precursors exhibit suppressive effects on the CD8 response. These findings elucidate a previously unappreciated axis of neuroimmune coordination in cancer and are pivotal to understanding crucial elements of tumor progression that will help shape the course of targeted immunotherapies in the future.