Vitamin B6 Modulates NK Cell Metabolism in Pancreatic Cancer

维生素 B6 调节胰腺癌 NK 细胞代谢

基本信息

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
项目类别：
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

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

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项目摘要

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存活率较差，部分原因是对现有疗法的反应。因此，迫切需要开发新的疗法。基于NK细胞的疗法提出有前途的选择，因为NK细胞主要通过直接杀伤或IFN-Gamma靶向肿瘤细胞生产，不依赖于MHC表达。但是，在肿瘤微环境中，NK细胞直接与肿瘤细胞竞争营养，以维持基础细胞代谢。值得注意的是，细胞代谢途径与NK细胞的效应子响应紧密相关。肿瘤教育的NK细胞表明增加糖酵解，增强其细胞毒性活性。但是，代谢的完整谱在NK细胞中重新编程尚不完全了解。胰腺肿瘤是高糖酵解的。肿瘤细胞表现出对葡萄糖或谷氨酰胺的需求不断增加，以促进合成代谢需求并耗尽基本营养素肿瘤微环境环境。营养饥饿会触发代谢改变，以支持增殖和胰腺肿瘤的侵略性表型。因此，胰腺肿瘤微环境显示营养贫苦，限制了NK细胞中的代谢通量。我们的初步数据表明维生素B6在 NK肿瘤细胞共培养成为NK细胞对胰腺反应的抗肿瘤反应的限制因素肿瘤细胞和类器官。此外，维生素B6的衰弱和葡萄糖限制会诱导代谢重新布线 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的全身性不平衡。我们观察到全身维生素B6代谢物在 PDAC患者。此外，我们证明胰腺肿瘤细胞显示出代谢通量增加，并且对NK细胞可分配的代谢途径的依赖，提供了代谢脆弱性可以与补充维生素B6联合靶向。总之，我们认为胰腺肿瘤细胞在肿瘤微环境环境中耗尽维生素B6，影响细胞代谢并诱导NK 细胞功能障碍。我们将检查（特定目标1）有利于肿瘤细胞介导的维生素的代谢途径 PDAC TME环境中的B6精疲力尽，可在营养限制条件下维持肿瘤细胞的增殖。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调节NK细胞在2D培养物，器官和原位小鼠模型中的抗肿瘤反应。我们还将检查靶向肿瘤细胞选择性代谢依赖性的治疗潜力，与补充维生素B6的结合，在肿瘤中的营养限制的背景下原位和患者衍生的异种移植模型中的微环境（特定目标3）。总体而言，我们的研究将研究胰腺癌细胞和NK细胞之间的代谢竞争，以理解从长远来看，选择性代谢脆弱性用于开发基于NK的强大疗法。