Adrenergic stress misdirects erythropoiesis compromising cancer immunity

Abstract Psychological stress is well known to cause weaker immunity. Stress, through the hypothalamus-pituitary-adrenal axis, induces secretion of cortisol, which causes immune suppression. Recently, stress-induced adrenergic mechanisms have begun to be shown to mediate immune suppression. Our work here reveals a novel axis whereby stress modulates erythropoiesis via the fight-or-flight hormones, and through it, immune suppression. Elevated levels of catecholamines, acting through 2-adrenergic receptors on precursor cells in erythroid differentiation, mis-direct erythroid differentiation causing accumulation of aberrant erythroid precursor cells (EPC) in mice as well as humans. EPC suppress priming as well as expansion of the CD8+ T cell response through their effect on dendritic cells (DC); EPC trogocytose cell surface MHC I from DC, and DC exposed to EPC are less effective at T cell activation. EPC suppress tumor immunity in several models and this suppression is exacerbated during adrenergic stress. The magnitude of suppression of tumor immunity by EPC is comparable to that mediated by regulatory T cells. Higher expression of CD71, a marker for EPC, is associated with poor overall and disease free survival in many human cancers. Our results uncover a role for adrenergic signaling in erythropoiesis, and establish erythroid cells, in addition to the lymphoid and myeloid cells, as significant determinants of cancer immunity.