The role of sympathetic nerve associated macrophages during pancreatic adenocarcinoma progression

交感神经相关巨噬细胞在胰腺腺癌进展中的作用

• 批准号: 10653062
• 负责人: Jonathan Robert Weitz
• 金额: $ 7.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10653062
• 关键词: Acetylcholine; Adoptive Transfer; Adrenergic Agents; Adrenergic Receptor; Antitumor Response; Autonomic nervous system; Binding; Biology; Bone Marrow; Cancer Model; Cell Communication; Cell Proliferation; Cell physiology; Cell surface; Cells; Communication; Complex; Data; Disease; Doctor of Philosophy; Enzymes; Failure; Genes; Histologic; Human; Immune; Immune system; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Situ; Incidence; Intervention Studies; Invaded; Investigation; KPC model; Knock-out; Label; Macrophage; Malignant Neoplasms; Mediating; Methaqualone; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Nerve; Nerve Fibers; Neuroimmune; Neurons; Neurotransmitters; Norepinephrine; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Paracrine Communication; Patient-Focused Outcomes; Patients; Physiological; Play; Population; Process; Production; Prognostic Factor; Role; Signal Transduction; Site; Slice; Tissues; Tumor Cell Invasion; Tumor Promotion; Tumor-infiltrating immune cells; Visualization; Work; adrenergic block; autonomic nerve; cellular targeting; chemical release; chemokine; clinical investigation; cytokine; glial cell-line derived neurotrophic factor; human tissue; immune function; immunogenicity; improved; in vivo; mortality; mouse model; nano-string; neoplastic cell; neural; neurotransmitter release; novel therapeutic intervention; pancreatic cancer model; pancreatic neoplasm; perineural; reconstruction; response; technology platform; tool; transcriptomics; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic

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.

项目概要/摘要 胰腺导管腺癌（PDAC）是所有主要癌症中死亡率最高的。尽管 免疫疗法彻底改变了许多癌症的治疗方法，例如胰腺癌患者的治疗方法 导管腺癌（PDAC）尚未成功。当前免疫治疗方法的失败 是由于胰腺肿瘤的许多特征造成的，包括：免疫原性差且高度 免疫抑制肿瘤微环境（TME）。巨噬细胞被认为是一个焦点 PDAC 期间的介入研究，因为它们调节免疫抑制，促进促纤维化 微环境，并在促进肿瘤沿局部神经进展中发挥重要作用。这 自主神经系统与局部巨噬细胞密切合作。刺激自主神经 然而，巨噬细胞中细胞因子和趋化因子的产生有助于其上述功能， 神经与免疫系统沟通并协调释放的信号机制 致瘤因素尚不清楚。根据我们的初步数据，我推测去甲肾上腺素 (NA) 释放 来自交感神经与交感神经相关巨噬细胞（SAM）上的肾上腺素能受体结合， 因此支持肿瘤进展。研究局部胰神经之间的通讯 和免疫细胞，我们使用来自人和小鼠 PDAC 肿瘤的离体胰腺组织切片。有了这个 技术平台，我们能够以最小的破坏可视化神经、巨噬细胞和肿瘤细胞 从他们的自然状态。我们将表征巨噬细胞中响应自主神经的 [Ca2+]i 反应 神经递质，以及使用有针对性的体内方法来确定是否阻断肾上腺素能 免疫细胞内的信号传导促进抗肿瘤反应。结合我们初步的生理数据， 我们将使用分子方法进一步探索这种串扰。我们希望我们的结果能够确定 PDAC背景下巨噬细胞、肿瘤细胞和自主神经之间的通讯网络 神经周围的侵袭将促进这种致命疾病的新治疗方法。