The Immunomodulatory Effects of Nrf2 Activation on Macrophages in the Lung Tumor Microenvironment

Nrf2 激活对肺肿瘤微环境中巨噬细胞的免疫调节作用

基本信息

批准号：
10678092
负责人：
Jessica Ann Moerland
金额：
$ 4.18万
依托单位：
MICHIGAN STATE UNIVERSITY
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：
2023-08-16 至 2025-05-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678092
关键词：
Affect Angiogenic Factor Anti-Inflammatory Agents Biological Models Bone Marrow CRISPR/Cas technology Cancer Biology Cancer Etiology Cancer Patient Cell Survival Cells Cessation of life Chemoresistance Chemotactic Factors Clinical Clinical Trials Cysteine Cytoprotection Data Defense Mechanisms Development Disease Educational process of instructing Environment Esters Flow Cytometry Genes Human Imaging Techniques Immune In Vitro Infiltration Inflammatory Injections Knock-out Knockout Mice Learning Lung Lung Adenocarcinoma Lung Neoplasms Macrophage Macrophage Activation Malignant Neoplasms Malignant neoplasm of lung Modeling Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Normal Cell Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Reporting Research Personnel Role Signal Pathway Survival Rate Techniques Terpenes Testing Training Tumor Burden Tumor Promotion Tumor-associated macrophages United States Wild Type Mouse anti-cancer anti-tumor immune response anticancer research antitumor effect cancer cell cancer prevention cancer therapy career cell type experimental study genome editing immune cell infiltrate immunoregulation in vivo in vivo Model in vivo imaging ineffective therapies inflammatory marker inflammatory milieu knockout gene lung carcinogenesis mouse model neoplastic cell novel novel therapeutics oleanane patient biomarkers patient prognosis patient response pharmacologic polarized cell pre-clinical preclinical study protective pathway recruit skills success therapeutic target transcriptomics tumor tumor growth tumor microenvironment tumor progression tumorigenic ultrasound

项目摘要

Project Summary There is a critical need for the development of new therapies for lung cancer, as current treatments are ineffective and the five-year survival rate remains below 20%. The immune infiltrate in the lung tumor microenvironment is a promising target for anti-cancer therapy. Macrophages make up the majority of this immune population and exist on a dynamic spectrum which can either be anti-cancer or cancer-promoting. In developed tumors, a pro- inflammatory phenotype in macrophages is beneficial for an anti-tumor immune response. To survive in this inflammatory environment, macrophages rely on cytoprotective mechanisms regulated by the Nrf2 pathway. This pathway serves as a defense mechanism against oxidative stress and protects normal, healthy cells from malignant transformation. While constitutive Nrf2 activation in tumor cells can aid tumor cell survival, the effect that Nrf2 activation has on immune cells in the tumor microenvironment is surprisingly underexplored. Synthetic derivatives of oleanane triterpenoids are the most potent known pharmacological activators of the Nrf2 pathway, and the triterpenoid CDDO-Methyl ester (CDDO-Me) has potent anti-tumor activity in a preclinical mouse model of lung cancer. Tumor-educated bone marrow-derived macrophages (BMDMs) increase pro-inflammatory markers associated with an anti-tumor immune response and decrease pro-tumor chemotactic and angiogenic factors when treated with CDDO-Me. Therefore, I hypothesize that by inducing an anti-tumor macrophage phenotype within the tumor microenvironment, Nrf2 activation will decrease lung tumor burden. Aim 1 of this proposal will determine if Nrf2 activation in macrophages increases their anti-tumor function. Aim 2 will evaluate whether Nrf2 activation in tumor cells polarizes tumor-associated macrophages to promote tumor growth and if pharmacological Nrf2 activation in the microenvironment can overcome the effect of Nrf2 activation in mutated tumor cells to reduce tumor burden. This proposal includes a comprehensive training plan including didactic and experimental learning in both in vitro and in vivo model systems, transcriptomics, genome editing, and novel in vivo imaging techniques. Completion of the proposed studies will provide me with the necessary skills and rigorous training needed for success as an independent and collaborative investigator in cancer biology.

项目摘要迫切需要开发新的肺癌疗法，因为目前的治疗效果无效五年生存率仍低于20％。肺肿瘤微环境中的免疫浸润是抗癌治疗的有希望的靶标。巨噬细胞构成了这种免疫种群的大多数存在于动态频谱上，可以是抗癌或癌症促进。在发达的肿瘤中巨噬细胞中的炎症表型对抗肿瘤免疫反应有益。为此生存炎症环境，巨噬细胞依赖于由NRF2途径调节的细胞保护机制。这途径是针对氧化应激的防御机制，并保护正常的健康细胞免受恶性转化。虽然肿瘤细胞中的构型NRF2激活可以帮助肿瘤细胞的存活 NRF2激活对肿瘤微环境中免疫细胞的活化具有令人惊讶的是没有被倍增。合成的丁香三萜的衍生物是NRF2途径的最有效的已知药理激活剂，三萜CDDO-甲基酯（CDDO-ME）在临床前小鼠模型中具有有效的抗肿瘤活性肺癌。受肿瘤教育的骨髓来源的巨噬细胞（BMDMS）增加促炎性与抗肿瘤免疫反应相关的标志物，并降低了肿瘤的趋化性和血管生成用CDDO-ME处理的因素。因此，我假设诱导抗肿瘤巨噬细胞肿瘤微环境中的表型，NRF2激活将减轻肺部肿瘤负担。目标1 建议将确定巨噬细胞中的NRF2激活是否会增加其抗肿瘤功能。 AIM 2将评估肿瘤细胞中NRF2激活是否会使肿瘤相关的巨噬细胞极化以促进肿瘤的生长以及if 微环境中的药理学NRF2激活可以克服NRF2激活在突变中的影响肿瘤细胞减轻肿瘤负担。该建议包括一个全面的培训计划，包括教学和体外和体内模型系统，转录组学，基因组编辑和新颖的实验学习体内成像技术。拟议研究的完成将为我提供必要的技能和作为癌症生物学独立和合作研究者成功所需的严格培训。