Understanding the Role of Macrophages and Iron in the Tumor Microenvironment

项目摘要/摘要 胶质母细胞瘤是现代医学面临的最具侵袭性和最难治疗的人类癌症之一。 目前对新诊断的胶质母细胞瘤的标准护理包括手术切除，然后是6 半个星期的同步放化疗和另外六个月的辅助治疗 化疗。尽管采取了这种积极的、令人精疲力竭的治疗方案，但大多数患者将遭受 肿瘤复发，近90%将在最初诊断的5年内消失。这些惨淡的存活率 提示胶质母细胞瘤具有抵抗现有治疗方法的机制。 近年来，肿瘤微环境在肿瘤治疗中的重要作用越来越受到人们的重视。 在支持癌细胞方面发挥作用。巨噬细胞在肿瘤微环境中扮演着特别重要的角色。 无论是在体积上还是在功能上。这些细胞影响肿瘤微环境的多个方面。 包括抑制抗肿瘤免疫和控制肿瘤内的铁代谢。铁是一种 癌细胞为促进其增殖所必需的营养物质。没有铁，癌细胞就不能增殖。 目前尚不清楚放疗和化疗如何影响体内的铁代谢。 巨噬细胞和其他免疫细胞在胶质母细胞瘤的肿瘤微环境中渗透。目标1 该项目将阐明铁的新陈代谢是如何因放射和化疗而改变的，并将 将这些变化与抗肿瘤免疫的变化联系起来。该项目的目标2将研究如何静脉注射 传递的铁化合物影响巨噬细胞内的铁代谢和免疫功能等关键因素 肿瘤微环境中的免疫细胞。此外，Aim 2将调查静脉注射铁是如何 改变肿瘤微环境内的血管系统。贫血是癌症中常见的并存疾病。 经常用静脉补铁纠正的患者。尽管如此，人们对静脉注射的影响知之甚少 铁对上述肿瘤微环境有重要影响。该项目将深化我们的 对化疗、放疗和静脉铁支持治疗如何影响肿瘤的理解 希望确定基于铁的治疗耐药机制。重要的是，铁的进展 补充剂、螯合剂和基因疗法使基于铁的治疗耐药机制大有希望 临床目标，以提高我们目前对胶质母细胞瘤的护理标准。

PROJECT SUMMARY/ABSTRACT Glioblastoma is one of the most aggressive and hard to treat human cancers facing modern medicine. The current standard of care for a new diagnosis of glioblastoma consists of surgical resection followed by a six and half weeklong course of concomitant chemo-radiation and another six-month-long course of adjuvant chemotherapy. Despite this aggressive and grueling treatment regimen, the majority of patients will suffer from tumor recurrence and nearly 90% will pass away within 5 years of initial diagnosis. These dismal survival rates indicate that glioblastoma possess mechanisms to resist current treatments. In recent years, the tumor microenvironment has increasingly been recognized for the essential role it plays in supporting cancer cells. Macrophages play a particularly important role in the tumor microenvironment both in terms of volume and function. These cells impact multiple aspects of the tumor microenvironment including suppressing anti-tumor immunity and controlling iron metabolism within the tumor niche. Iron is an essential nutrient required by cancer cells to fuel their proliferation. Without iron, cancer cells cannot proliferate. It is currently unknown how treatment with radiation and chemotherapy impact iron metabolism within macrophages and other infiltrating immune cells within the tumor microenvironment of glioblastoma. Aim 1 of this project will elucidate how iron metabolism is altered as a result of radiation and chemotherapy and will correlate these alterations to changes in anti-tumor immunity. Aim 2 of this project will study how intravenously delivered iron compounds impact iron metabolism and immune function within macrophages and other key immune cells within the tumor microenvironment. Additionally, aim 2 will investigate how administration of IV iron alters the vasculature within the tumor microenvironment. Anemia is a common co-morbidity among cancer patients that is frequently corrected with intravenous iron. Despite this, little is known regarding the effects of IV iron on the above-mentioned important aspects of the tumor microenvironment. This project will deepen our understanding of how treatments with chemotherapy, radiation, and supporting intravenous iron impact tumors with the hopes of identifying iron-based mechanisms of treatment resistance. Importantly, advances in iron supplements, chelators, and gene therapies make iron-based mechanisms of treatment resistance promising clinical targets to improve our current standard of care for glioblastoma.