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  • br As tumors need to re develop a


    As tumors need to re-develop a vascular network to ensure nutrition and communication, neural input may provide a critical set of signals that coordinate cancer progression (Sica et al., 2008). Numerous studies have shown that stress-related catecholamines might act as a crucial factor in regulating tumor growth by promoting angiogenesis (Chen et al., 2018). Animal tumor models suggest that TAMs’ depletion in-hibits angiogenesis and tumor growth, whereas increased amounts of TAMs exhibit the opposite effects. Preclinical trials report that ARs have critical roles in NE-induced VEGF expression in cancer cells, resulting in the stimulation of angiogenesis (Park et al., 2011; Yang et al., 2009). Our work also supported an adrenergic signaling-dependent mechanism where NE and EPI potently acted on the adrenergic receptors of mac-rophages to stimulate the secretion of VEGF, which promoted angio-genesis for lung cancer growth. In addition, the ablation of the sym-pathetic function by 6OHDA or blockage of the adrenergic signaling by propranolol in competition with adrenergic receptor-stimulating agents suppressed stress-induced lung cancer growth remarkably. These results provide a new insight into the dynamic nature of TAMs during tumor growth and support the claim that catecholamines can function as a key factor in macrophages polarization, tumor angiogenesis, and immune defense.
    Interactions between neurons and immune KPT330 are multifactorial and multidimensional. Stimulation of adrenergic signaling not only regulates cell development, trafficking for immune surveillance, but also directs the cell-to-cell interactions necessary for a coordinated immune response. The expression of receptors for neurotransmitters has been identified on TAMs, MDSCs, NKs, DCs as well as other immune cells (Herve et al., 2013; Jin et al., 2013), which collectively facilitate the neural regulation of immune responses in a more complex neu-roimmunomodulatory circuitry (Chavan et al., 2017). In order to elu-cidate the impact of catecholamines on localized and systematic im-mune systems, peripheral blood and sympathetic target organs, including tumor tissues and the best-defined lymphoid organs spleen, were analyzed in our study. Although there was no significant differ-ence in peripheral blood and spleens, our results revealed a clear effect at localized targets. As the critical immunocytes in innate and adaptive immunity, NKs, DCs and another major immunosuppressive myeloid cell population MDSCs were monitored in our investigation. Inhibition of adrenergic signaling could facilitate the immunologically active conversion of tumors with the decreased immunosuppressive MDSCs and increased active DCs, suggesting a shift from passive response to positive defense.
    Although blocking the adrenergic signaling could delay tumor growth in both types of lung cancers, the difference in the inhibition rates between SCLC and NSCLC should be noted. Based on our results, H446, the SCLC cell line responded better to the treatment targeting adrenergic signaling for a greater tumor regression, a lower secretion of VEGF, and a higher radio of M1/M2 after 6OHDA injection. Supporting this observation were the lower catecholamine concentrations, more remarkable decreased MVD of tumors, as well as the extent of increased active DCs and decreased MDSCs. Some works notice that catechola-mines have a widely negative impact on immune cells’ activity, in-cluding the mobilization and recruitment of macrophages, NKs, and DCs in circulation and in lymphoid tissues (Herve et al., 2013; Nissen et al., 2018). Such results were not observed in the peripheral blood and spleens in our study probably due to the incomplete clearance of the  Brain, Behavior, and Immunity xxx (xxxx) xxx–xxx
    catecholamine stock with 6OHDA.
    Despite our promising findings, it is hard to say whether the stricter control of local catecholamines in tumors or the biological differences within lung cancer types decides the better efficiency in H446. Further research is required to distinguish the dynamic tumor microenviron-ment and to explore the underlying mechanisms between SCLC and NSCLC. Additionally, there are some limitations in our experiments. For the systematic effects of catecholamines, more examinations focused on the sites beyond tumors need to be tested, especially some critical statistical significances were found in splenic active DCs (P = 0.06 for H446) and in circulating NKs (P = 0.06 for H446). Enzymatic digestion was used to isolate macrophages from tumor, and this procedure has been reported to help macrophages produce more cytokines such as IL-6, IL-10 and TNF-a, indicating a change of their functional activity (Bryniarski et al., 2005; Bryniarski et al., 2005). Although the digestion time and the whole experiment was controlled to minimize the impact, whether collagenase treatment influences the macrophage phenotype is still unknown, more critical evaluation of the method should be re-quired. Besides, we lacked the orthotopic injection models and the functional verification of infiltrating immune cells to investigate the natural environment in lungs. Despite these limitations, our findings still demonstrate that SNS can impact tumor progression substantially and that such effects are associated with significant alterations in host immune function. These finding set preclinical foundations to the po-tential utility of anti-neurogenic therapies.