The role of sympathetic nerve associated macrophages during pancreatic adenocarcinoma progression

项目摘要/摘要 胰腺导管腺癌(PDAC)是所有主要癌症中死亡率最高的。而当 免疫疗法已经彻底改变了许多癌症的治疗方法，比如胰腺癌患者的治疗。 导管腺癌(PDAC)的治疗一直没有成功。当前免疫治疗方法的失败 是由于胰腺肿瘤的许多特征所致，包括免疫原性差和高度 免疫抑制肿瘤微环境(TME)。巨噬细胞被认为是 PDAC期间的干预性研究表明，它们调节免疫抑制，促进促纤维化 微环境以及在促进肿瘤沿局部神经进展方面起着至关重要的作用。这个 自主神经系统与局部巨噬细胞密切合作。自主神经刺激 巨噬细胞产生的细胞因子和趋化因子有助于其上述功能，然而， 神经与免疫系统沟通并协调释放的信号机制 致癌因素尚不清楚。根据我们的初步数据，我推测去甲肾上腺素(NA)释放 从交感神经结合到交感神经相关巨噬细胞上的肾上腺素能受体， 从而支持肿瘤的发展。研究局部胰腺神经之间的交通 和免疫细胞，我们正在使用来自人和小鼠PDAC肿瘤的体外胰腺组织切片。有了这个 技术平台，我们能够以最小的干扰可视化神经、巨噬细胞和肿瘤细胞 从它们的自然状态。我们将描述巨噬细胞对自主神经的反应。 神经递质，以及使用体内靶向方法，以确定是否阻断肾上腺素能 免疫细胞内的信号促进抗肿瘤反应。结合我们的初步生理数据， 我们将使用分子方法来进一步探索这种串扰。我们希望我们的结果能确定 PDAC环境下巨噬细胞、肿瘤细胞和自主神经之间的通讯网络 神经侵袭将促使这种致命疾病的新的治疗方法。

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancers. While immunotherapy has revolutionized treatment for numerous cancers, such treatments for patients with pancreatic ductal adenocarcinoma (PDAC) have not been successful. Failure of the current immunotherapeutic approaches are due to numerous features of pancreatic tumors including; poor immunogenicity and a highly immunosuppressive tumor microenvironment (TME). Macrophages are considered as a focal point for interventional studies during PDAC given that they regulate immunosuppression, promote a pro-fibrotic microenvironment, as well as play an essential role in promoting tumor progression along local nerves. The autonomic nervous system work in close partnership with local macrophages. Autonomic nerves stimulate cytokine and chemokine production in macrophages that contribute to their aforementioned functions, however, the signaling mechanisms by which nerves communicate with the immune system and coordinate the release of tumorigenic factors are unknown. Based on our preliminary data, I hypothesize that noradrenaline (NA) released from sympathetic nerves binds to adrenergic receptors on sympathetic nerve associated macrophages (SAMs), which consequently support tumor progression. To study the communication between local pancreatic nerves and immune cells, we are using ex vivo pancreatic tissue slices from human and mouse PDAC tumors. With this technological platform, we are able to visualize nerves, macrophages, and tumor cells with minimal disruption from their natural state. We will characterize [Ca2+]i responses in macrophages in response to autonomic neurotransmitters, as well as use a targeted in-vivo approach in order to determine if blocking adrenergic signaling within immune cells promotes anti-tumor responses. Combined with our preliminary physiological data, we will use molecular approaches to further explore this crosstalk. We expect our results to identify communication networks between macrophages, tumor cells and autonomic nerves in the setting of PDAC perineural invasion that will prompt new therapeutic approaches for this deadly disease.