Beta-adrenergic mediated suppression of T cell chemotaxis by cancers

摘要 肿瘤生长诱导局部和全身免疫抑制作用， 肿瘤的浸润，从而限制了基于T细胞的免疫疗法的效果。 表明干扰素信号传导和CXCR 3下游表达的恢复 同源趋化因子足以恢复肿瘤的T细胞浸润。然而，机制 在肿瘤中调节趋化因子产生和T细胞浸润的机制仍然不清楚。 最近的研究报道，小鼠保持在标准饲养温度（ST 条件下，~24°C）经历慢性冷应激和β-肾上腺素能信号传导的诱导， 包括诱导高水平的循环去甲肾上腺素（NE），相对于维持 在热中性（TN）条件下（28-30°C）。值得注意的是，肿瘤在ST- 条件小鼠，同时减少CD 8浸润和趋化因子产生。因此，在本发明中， ST小鼠中的肿瘤在免疫学上类似于患者来源的样品（NE充满和缺乏 趋化因子和T细胞浸润），这表明应激诱导的信号通路可能发挥作用， 在限制对肿瘤的免疫反应中起主要作用。我们认为β-肾上腺素能信号 抑制干扰素和干扰素诱导的趋化因子的产生（包括CXCR 3同源物 趋化因子CXCL 9和CXCL 10），从而限制CXCR 3 + CD 8 T细胞浸润和免疫介导的肿瘤排斥反应。进一步说，阻断肾上腺素能 信号传导可以诱导或恢复干扰素诱导的趋化因子的产生和CXCR 3 + T细胞 肿瘤浸润。在这项探索性/发展性研究中，我们将1）研究神经元的作用- 肾上腺素能信号在调节趋化因子产生和T细胞向黑色素瘤运输中的作用 微环境;和2）评估β-肾上腺素能信号传导对基于T细胞的疗法的影响 治疗癌症这些研究将为未来R 01规模的特定分子和 肿瘤微环境中应激介导变化的细胞作用机制，以及 为将这些临床前研究转化为临床0/1期试验提供概念基础， 以增强T细胞浸润为目的的联合收割机肿瘤阻断剂和癌症免疫疗法 和抗肿瘤功效。

ABSTRACT Tumor growth induces local and systemic immunosuppressive effects that diminish immune cell infiltrationoftumors,therebylimitingtheefficacyofTcell-basedimmunotherapies.Wepreviously demonstrated that restoration of interferon signaling and downstream expression of CXCR3 cognate chemokines is sufficient to restore T cell infiltration of tumors. However, the mechanisms that modulate chemokine production and T cell infiltration in tumors remain poorly defined. Recent studies have reported that mice maintained at standard vivarium temperatures (ST conditions, ~24°C) experience chronic cold stress and induction of -adrenergic signaling, including induction of high levels of circulating norepinephrine (NE), relative to mice maintained in thermoneutral (TN) conditions (28-30°C). Significantly, tumors grow more rapidly in ST- conditioned mice, concurrent with reduced CD8 infiltration and chemokine production. Thus, tumors in ST mice immunologically resemble patient-derived samples (NE replete and lacking chemokine and T cell infiltrates), suggesting that stress-induced signaling pathways may play a major role in limiting immune responses to tumors. We propose that -adrenergic signaling suppresses interferon and interferon-inducible chemokine production (including CXCR3-cognate chemokines CXCL9 and CXCL10) in the tumor microenvironment, thereby limiting CXCR3+CD8 T cell infiltration and immune-mediated tumor rejection. By extension, blocking -adrenergic signaling may induce or restore interferon-inducible chemokine production and CXCR3+ T cell infiltration in tumors. In this exploratory/developmental study, we will 1) investigate the role of - adrenergic signaling in regulation of chemokine production and T cell trafficking to the melanoma microenvironment; and 2) assess the impact of -adrenergic signaling on T cell-based therapies for cancer. These studies will inform future R01-scale investigations of the specific molecular and cellular mechanisms of action in stress-mediated changes in the tumor microenvironment, and provide a conceptual basis to translate these preclinical studies into clinical Phase 0/1 trials that combine -blockers and cancer immunotherapy for the purpose of enhancing T cell infiltration and anti-tumor efficacy.