Understanding the Role of Macrophages and Iron in the Tumor Microenvironment

了解巨噬细胞和铁在肿瘤微环境中的作用

基本信息

批准号：
10388113
负责人：
Ganesh J Shenoy
金额：
$ 5.18万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388113
关键词：
Activities of Daily Living Adjuvant Chemotherapy Aftercare Alkylating Agents Anemia Animals Biological Assay Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Patient Cell Proliferation Cells Chelating Agents Chemotherapy and/or radiation Chemotherapy-Oncologic Procedure Clinical Confocal Microscopy Diagnosis Excision Flow Cytometry Formulation Genes Glioblastoma Glioma Growth Human Immune Immunofluorescence Microscopy In Vitro Intravenous Iron Iron Compounds Knowledge Malignant Neoplasms Measures Modern Medicine Mus Myeloid-derived suppressor cells Natural Killer Cells Nutrient Operative Surgical Procedures Patients Phenotype Play Population Proliferating Radiation therapy Radiometry Recurrence Regulation Reporting Role Sampling Solid Neoplasm Supporting Cell Survival Rate Techniques Testing Treatment Protocols Tumor Immunity Tumor Volume Tumor-infiltrating immune cells base cancer cell cancer therapy chemoradiation chemotherapy clinically relevant comorbidity cytokine exhaust experimental study ferryl iron gene therapy immune function immunosuppressive macrophages improved in vitro Model in vivo insight interest iron metabolism iron supplement iron supplementation macrophage mouse model radiation effect standard of care temozolomide therapy resistant trafficking transcriptomics treatment effect treatment group treatment response tumor tumor growth tumor microenvironment

项目摘要

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.

项目概要/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。当前新诊断的胶质母细胞瘤的护理标准包括手术切除，然后进行六次手术半周的同步放化疗疗程和另外六个月的辅助疗程化疗。尽管采取了这种积极而艰苦的治疗方案，但大多数患者仍会遭受以下痛苦：肿瘤复发，近90%会在初次诊断后5年内死亡。这些惨淡的生存率表明胶质母细胞瘤具有抵抗当前治疗的机制。近年来，人们越来越认识到肿瘤微环境在肿瘤发生中的重要作用。发挥支持癌细胞的作用。巨噬细胞在肿瘤微环境中发挥着特别重要的作用无论是在体积还是功能上。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微环境内的铁代谢。铁是一种癌细胞促进其增殖所需的必需营养素。没有铁，癌细胞就无法增殖。目前尚不清楚放疗和化疗治疗如何影响体内铁代谢胶质母细胞瘤的肿瘤微环境内的巨噬细胞和其他浸润免疫细胞。目标 1 的该项目将阐明放疗和化疗如何改变铁代谢，并将将这些改变与抗肿瘤免疫的变化相关联。该项目的目标 2 将研究如何通过静脉注射递送的铁化合物影响巨噬细胞和其他关键细胞内的铁代谢和免疫功能肿瘤微环境中的免疫细胞。此外，目标 2 将研究如何给予静脉铁剂改变肿瘤微环境内的脉管系统。贫血是癌症中常见的并发症经常通过静脉补铁来纠正的患者。尽管如此，人们对 IV 的影响知之甚少。铁对肿瘤微环境的上述重要方面的影响。这个项目将加深我们了解化疗、放疗和辅助静脉铁剂治疗如何影响肿瘤希望能够确定基于铁的治疗耐药机制。重要的是，铁的进步补充剂、螯合剂和基因疗法使基于铁的治疗耐药机制前景光明提高我们当前胶质母细胞瘤护理标准的临床目标。