Destress and do not suppress: targeting adrenergic signaling in tumor immunosuppression

Abstract

Tumor-induced immunosuppression is a common obstacle for cancer treatment. Adrenergic signaling triggered by chronic stress participates in the creation of an immunosuppressive microenvironment by promoting myeloid-derived suppressor cell (MDSC) proliferation and activation. In this issue of the JCI, Mohammadpour et al. elegantly delve into the mechanisms underlying MDSC contribution to tumor development. They used in vitro and in vivo mouse models to demonstrate that chronic stress results in MDSC accumulation, survival, and immune-inhibitory activity. Of therapeutic relevance, the authors showed that propranolol, a commonly prescribed β-blocker, can reduce MDSC immunosuppression and enhance the effect of other cancer therapies.

Figure 1. Schematic representation of adrenergic stress upon MDSC physiology.

Subthermoneutral housing induces adrenergic β2-AR–mediated stress. Adrenergic stress alters MDSC physiology and enhances MDSC protumoral-immunosuppressive signaling. MDSCs from β2-AR^–/– mice fail to respond to adrenergic stress, which attenuates the immunosuppressive phenotype. β-enhancers, such as isoproterenol, enhance protumoral responses while the β-blocker propranolol alleviates protumoral phenotype in WT mice.