Activation of hypothalamic μ-opioidergic system enhances the anti-tumor immune response

[Speaker] Yusuke Hamada:1
[Co-author] Naomi Kanao:1, Sara Yoshida:1, Michiko Narita:1, Hideki Tamura:2, Hiroyuki Tezuka:2, Masami Suzuki:3, Akihiro Yamanaka:4, Naoko Kuzumaki:1, Minoru Narita:1,2
1:Dept. Pharmacology, Hoshi University, Japan, 2:L-StaR, Hoshi University, Japan, 3:Div. Cancer Genomics, NCCRI, Japan, 4:Dept. Neuroscience II, RIEM, Nagoya University, Japan

 Recent studies have shown that chronic stressful conditions or depression, could suppress the systemic immune response. In contrast, emerging evidence from the field of reward research has shown that positive stimulation, such as pleasant sensations, could enhance the immune response to pathogens on an empirical basis. Therefore, we hypothesized that crosstalk between changes in the central function and the peripheral immune regulation could be crucial for tumor progression. On the other hand, the neural regulation in the hypothalamic paraventricular nucleus (PVN) is known to have the ability to change the innate endocrine and immune functions. Notably, it has been reported that μ-opioid receptor (MOR) is highly expressed in the PVN, but its physiological function remains unclear. In this study, we investigated the role of the activation of hypothalamic μ-opioidergic system in an anti-tumor immune response using designer receptors exclusively activated by designer drugs (DREADD) technology. To perform the activation of hypothalamic μ-opioidergic system, we generated transgenic mice specifically expressing Gq-coupled human muscarinic M3 DREADD (hM3Dq) protein in the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), which can release an endogenous MOR-ligand β-endorphin. Under these conditions, the activation of POMC neurons in the ARC significantly suppressed tumor growth via the activation of cell-mediated immunity. This phenomenon was reversed by the MOR-antagonist naloxone injected into the PVN. These findings suggest that the activation of hypothalamic μ-opioidergic system could directly suppress tumor growth through facilitating the anti-tumor immune response.
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