β-adrenergic signaling regulates erythropoiesis and through it; cancer immunity

The intricate interplay between the nervous and immune systems significantly influences the fate of immune cells in homeostasis as well as under pathological conditions such as cancer. Notably, adrenergic signals from the sympathetic nervous system have been identified as regulators of hematopoiesis. Disruption of sympathetic signaling has been linked to mal-differentiation of myeloid and lymphoid lineages leading to the emergence of Tregs, myeloid-derived suppressor cells, and the exhaustion of CD8+ T cells. We show here that disrupted sympathetic signaling also leads to mal-differentiation of erythroid lineage via the emergence of erythroid precursor cells (EPCs), which, apart from their role in maintenance of the red blood cell pool, contribute significantly to suppression of the anti-tumor CD8+ T cell response.

Specifically, we show here that EPCs are highly regulated by β-adrenergic signaling in naïve as well as tumor-bearing mice. We observe that EPCs actively promote tumor growth in vivo and influence the fate of tumor infiltrating CD8+ T cells by suppressing their proliferation and effector functions. We have reported several aspects of the mechanisms involved in the β-adrenergic regulation of erythropoiesis including the specific receptors involved, the signaling pathway and the kinetics of the effect. This discovery unveils a novel dimension of neuroimmune communication and offers insights that could catalyze the development of new therapeutic approaches to cancer.