Adrenergic signaling activates the tumor immune microenvironment in Multiple Myeloma

Adrenergic signaling regulated by cortisol, norepinephrine and epinephrine controls a variety of physiological processes. Preclinical studies demonstrated that adrenergic signaling promotes tumor progression and negatively affects the anti-tumor immune response in solid tumor models. Since Multiple Myeloma (MM), a hematological cancer, is typically treated with immunotherapy nowadays; we aimed to reveal the impact of chronic restraint stress (CRS) on tumor load and the immune microenvironment during MM disease progression. To recapitulate CRS, naïve and 5T33MM-bearing mice were daily exposed to restraint stress starting 7 days prior to tumor inoculation. Effects on the immunological environment and tumor load were evaluated using multi-parameter flow cytometry. We found that CRS resulted in a significant reduction of tumor cells in the BM at end-stage of disease. CRS induced neutrophilia in the BM at 7 days post-tumor inoculation (DPI) and lymphocytosis (with increased CD8+ T cells, NK and NKT cells) in the spleen of MM-bearing mice at 14 DPI. In the splenic compartment, increased IFN-y expression, particularly by NK cells was observed. Similar results on neutrophils and lymphocytes were observed in naïve mice exposed to CRS for 7-28 days. Our findings unexpectedly demonstrate that adrenergic stimulation shifts the MM microenvironment towards an immune activated profile. This notion suggests pharmacological stimulation with adrenergic receptor agonists might increase the immunological response in MM and potentially improve the effects of current immunotherapies. Novel in vivo experiments evaluating the impact of adrenergic receptor agonists will be conducted to validate this hypothesis.