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: 10315610
• 负责人: Jonathan Robert Weitz
• 金额: $ 6.64万
• 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/10315610
• 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; Malignant Neoplasms; Matrix Metalloproteinases; 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-infiltrating immune cells; Work; adrenergic block; autonomic nerve; base; cellular targeting; chemical release; chemokine; clinical investigation; cytokine; glial cell-line derived neurotrophic factor; human tissue; immune function; immunogenicity; improved; in vivo; macrophage; mortality; mouse model; nano-string; neoplastic cell; neurotransmitter release; novel therapeutic intervention; pancreatic cancer model; pancreatic neoplasm; perineural; reconstruction; relating to nervous system; response; 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.

项目总结/文摘