Vitamin B6 Modulates NK Cell Metabolism in Pancreatic Cancer

维生素 B6 调节胰腺癌 NK 细胞代谢

• 批准号: 10568565
• 负责人: Kamiya Mehla
• 金额: $ 39.86万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568565
• 关键词: Activated Natural Killer Cell; Adenocarcinoma Cell; Adoptive Transfer; Allogenic; Anabolism; Antitumor Response; Attenuated; Biological Assay; Blood; Cancer Etiology; Carbon; Cell Degranulation; Cell Proliferation; Cell Survival; Cell Therapy; Cell physiology; Cells; Cellular Metabolic Process; Cellular immunotherapy; Cessation of life; Circulation; Coculture Techniques; Coenzyme A; Data; Dependence; Development; Diet; Exclusion; Exhibits; Frequencies; Functional disorder; Glucose; Glutamine; Glycine; Glycogen; Glycogen Phosphorylase; Glycogenolysis Induction; Glycolysis; Growth; Hydroxymethyltransferases; Hypoxia; Immune; Immunotherapy; Impairment; Incidence; Infusion procedures; Interferon Type II; Killer Cells; Kinetics; Knock-out; Kynurenine; Label; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Monitor; Mus; NADP; Natural Killer Cells; Nucleotides; Nutrient; Organoids; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phase; Phenotype; Play; Production; Prognostic Factor; Proliferating; Research Personnel; Risk; Role; Serine; Starvation; Supplementation; Survival Rate; T-Lymphocyte; Therapeutic; Therapeutic Studies; Treatment Efficacy; Tryptophan; Tumor Burden; Vitamin B 6 Deficiency; Vitamin B6; Vitamin B6 Metabolism Pathway; attenuation; cancer cell; chemotherapy; cofactor; cytotoxic; exhaust; exhaustion; glycogenolysis; immune function; improved; inhibitor; knock-down; mouse model; neoplastic cell; novel therapeutics; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; patient derived xenograft model; rapid growth; response; standard of care; success; tool; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

Project Summary: The poor survival rates in pancreatic ductal adenocarcinoma patients are in part due to poor response to existing therapies. Thus, there is an urgent need to develop novel therapies. NK cell-based therapies present a promising option because NK cells primarily target tumor cells through direct killing or IFN-gamma production and are not dependent on MHC expression. However, in the tumor microenvironment, NK cells directly compete with tumor cells for nutrients to maintain basal cellular metabolism. Of note, cellular metabolic pathways are closely linked with the effector response of NK cells. Tumor-educated NK cells demonstrate increased glycolysis, which potentiates their cytotoxic activity. However, the complete spectrum of metabolic reprogramming in NK cells is not fully understood. Pancreatic tumors are highly glycolytic. The tumor cells exhibit constant high demand for glucose or glutamine to fuel the anabolic needs and exhaust the essential nutrients in the tumor microenvironment milieu. Nutrient starvation triggers metabolic alterations to support proliferation and the aggressive phenotype of pancreatic tumors. Hence, the pancreatic tumor microenvironment displays nutrient paucity, which restricts the metabolic flux in NK cells. Our preliminary data suggest the scarcity of vitamin B6 in NK-tumor cell co-cultures becomes a limiting factor for the anti-tumor response of NK cells against pancreatic tumor cells and organoids. Furthermore, vitamin B6 paucity and glucose-limitation induce metabolic rewiring in NK cells to sustain glycolysis and downstream metabolic pathways. Of note, tumor progression causes a systemic imbalance of vitamin B6. We observed a significant reduction in systemic vitamin B6 metabolites in PDAC patients. Moreover, we demonstrate that pancreatic tumor cells display increased metabolic flux and dependence on metabolic pathways that are dispensable for NK cells, providing a metabolic vulnerability that can be targeted in combination with vitamin B6 supplementation. Taken together, we posit that pancreatic tumor cells exhaust vitamin B6 in the tumor microenvironment milieu, impacting cellular metabolism and inducing NK cell dysfunction. We will examine (Specific Aim 1) the metabolic pathways that favor tumor cell-mediated vitamin B6 exhaustion in the PDAC TME milieu to sustain tumor cell proliferation under nutrient-limiting conditions. In Specific Aim 2, we will investigate the functional significance of vitamin B6-induced metabolic remodeling in NKs that regulate the anti-tumor response of NK cells in 2D cultures, organoids, and orthotopic mouse models. We will also examine the therapeutic potential of targeting the selective metabolic dependencies of tumor cells, in combination with vitamin B6 supplementation, in the context of nutrient limitation in the tumor microenvironment in orthotopic and patient-derived xenograft models (Specific Aim 3). Overall, our study will investigate the metabolic competition between pancreatic cancer cells and NK cells for understanding the selective metabolic vulnerabilities for developing robust NK-based therapies in the long run.

项目摘要：胰腺导管腺癌患者的生存率较低，部分原因在于较差的治疗 对现有疗法的反应。因此，迫切需要开发新的疗法。基于 NK 细胞的疗法 提供了一个有前途的选择，因为 NK 细胞主要通过直接杀伤或 IFN-γ 来靶向肿瘤细胞 产生且不依赖于 MHC 表达。然而，在肿瘤微环境中，NK细胞 直接与肿瘤细胞竞争营养物质，维持基础细胞代谢。值得注意的是，细胞代谢 通路与 NK 细胞的效应反应密切相关。肿瘤培养的 NK 细胞证明 糖酵解增加，从而增强其细胞毒活性。然而，完整的代谢谱 NK 细胞的重编程尚不完全清楚。胰腺肿瘤是高度糖酵解的。肿瘤细胞表现出 对葡萄糖或谷氨酰胺的持续高需求来满足合成代谢的需要并耗尽体内的必需营养素 肿瘤微环境。营养饥饿会引发代谢改变以支持增殖和 胰腺肿瘤的侵袭性表型。因此，胰腺肿瘤微环境显示营养 缺乏，限制了 NK 细胞的代谢通量。我们的初步数据表明，维生素 B6 缺乏 NK-肿瘤细胞共培养成为 NK 细胞抗胰腺肿瘤反应的限制因素 肿瘤细胞和类器官。此外，维生素 B6 缺乏和葡萄糖限制会导致代谢重新布线 NK 细胞维持糖酵解和下游代谢途径。值得注意的是，肿瘤进展会导致 维生素B6的全身失衡。我们观察到全身维生素 B6 代谢物显着减少 PDAC 患者。此外，我们证明胰腺肿瘤细胞表现出增加的代谢通量和 对 NK 细胞来说可有可无的代谢途径的依赖，提供了代谢脆弱性 可以有针对性地结合维生素B6补充。综上所述，我们假设胰腺肿瘤 细胞耗尽肿瘤微环境中的维生素B6，影响细胞代谢并诱导NK 细胞功能障碍。我们将检查（具体目标 1）有利于肿瘤细胞介导的维生素的代谢途径 PDAC TME 环境中 B6 耗尽以在营养限制条件下维持肿瘤细胞增殖。在 具体目标 2，我们将研究维生素 B6 诱导的代谢重塑的功能意义 NK 在 2D 培养物、类器官和原位小鼠模型中调节 NK 细胞的抗肿瘤反应。 我们还将研究针对肿瘤细胞选择性代谢依赖性的治疗潜力， 在肿瘤营养有限的情况下，结合维生素 B6 补充剂 原位和患者来源的异种移植模型中的微环境（具体目标 3）。总的来说，我们的研究将 研究胰腺癌细胞和 NK 细胞之间的代谢竞争，以了解 从长远来看，选择性代谢脆弱性有助于开发基于 NK 的强大疗法。