Adrenergic signaling mediates immune suppression induced by cool housing temperatures for laboratory mice

Abstract

Abstract Our laboratory has demonstrated that standard mildly cool housing temperatures (ST, 22°C) can significantly enhance tumor growth by suppressing anti-tumor immunity. In contrast, we have found that maintaining mice at thermoneutral temperatures (TT, 30°C) reversed immunosuppression and significantly delayed tumor growth compared to ST. Under cool conditions, mammals produce heat via adaptive thermogenesis, a process which is driven by norepinephrine (NE) acting through β-adrenergic receptors (β-ARs) on brown adipose cells and we found that NE is significantly elevated in mice at ST compared to TT. NE is known to suppress immune cell activity. We therefore hypothesized that cool housing conditions elevate NE which then suppresses anti-tumor immunity. To investigate this hypothesis, we used two syngeneic mouse tumor models: 4T1 mammary carcinoma and B16-OVA melanoma. In tumor bearing mice at ST, the β-AR antagonist propranolol significantly delayed tumor growth. β-blockade had no effect on the growth of 4T1 tumors in immunodeficient SCID mice indicating a mechanism involving the adaptive immune response. In mice bearing B16-OVA tumors, β-blockade also slowed tumor growth and this beneficial effect was negated by CD8+ T-cell depletion. In both models, reversing adrenergic stress induced immunosuppression by β-AR blockade in combination with boosting the anti-tumor T cell response by blocking programmed cell death receptor 1 (PD-1) significantly slowed tumor growth in mice housed at ST compared to either treatment alone. Therefore, combination therapy with β-receptor antagonists could improve the clinical efficacy of immunotherapy, including checkpoint inhibition.