Vitamin B6 Modulates NK Cell Metabolism in Pancreatic Cancer

项目总结：胰腺导管腺癌患者的低生存率部分是由于 对现有疗法的反应。因此，迫切需要开发新的治疗方法。基于NK细胞的疗法 因为NK细胞主要通过直接杀伤或IFN-γ靶向肿瘤细胞， 它不依赖于MHC的表达。然而，在肿瘤微环境中，NK细胞 直接与肿瘤细胞竞争营养以维持基础细胞代谢。值得注意的是， 这些信号通路与NK细胞的效应子应答密切相关。受肿瘤训练的NK细胞显示 增加糖酵解，从而增强其细胞毒性活性。然而，代谢的完整谱 NK细胞中的重编程尚未完全理解。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，以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触发代谢改变以支持增殖， 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，这限制了NK细胞中的代谢通量。我们的初步数据表明， NK-肿瘤细胞共培养成为NK细胞对胰腺癌的抗肿瘤应答的限制因素。 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的系统性失衡。我们观察到， PDAC患者此外，我们证明胰腺肿瘤细胞显示代谢通量增加， 依赖于NK细胞的代谢途径，提供了一种代谢脆弱性， 可以与维生素B6补充剂结合使用。综合考虑，我们可以切除胰腺肿瘤 细胞在肿瘤微环境中耗尽维生素B6，影响细胞代谢并诱导NK 细胞功能障碍我们将研究（具体目标1）有利于肿瘤细胞介导的维生素C代谢途径。 PDAC TME环境中的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诱导的代谢重建在糖尿病中的功能意义。 在2D培养物、类器官和原位小鼠模型中调节NK细胞的抗肿瘤应答的NK。 我们还将研究靶向肿瘤细胞的选择性代谢依赖性的治疗潜力， 在肿瘤营养受限的情况下，与维生素B6补充剂联合使用 在原位和患者来源的异种移植物模型中的微环境（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， 从长远来看，选择性代谢的脆弱性，发展强大的NK为基础的疗法。

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.