Combating the Immunosuppressive Tumor Microenvironment in Triple Negative Breast Cancer: The Role of Mitochondrial Dynamics in the Polarization of Tumor-Associated Macrophages

对抗三阴性乳腺癌中的免疫抑制肿瘤微环境：线粒体动力学在肿瘤相关巨噬细胞极化中的作用

• 批准号: 10386645
• 负责人: Hilda Lyn Chan
• 金额: $ 5.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386645
• 关键词: Adopted; Aerobic; Anaerobic Bacteria; Anti-Inflammatory Agents; Cancer Etiology; Cancer Prognosis; Cancer Survivor; Categories; Cell physiology; Cessation of life; Characteristics; Complex; Data; Development; Diagnosis; Disease; Drug resistance; Electron Transport; Elements; Endocrine; Environment; Etiology; Female; Foundations; Gene Expression; Gene Expression Profile; Genes; Glycolysis; Goals; Growth; Human; Immune; Immunotherapy; Impairment; In Vitro; Inflammatory; Longevity; Mediating; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Mus; Neoplasm Metastasis; Oxidative Phosphorylation; Pathway interactions; Patients; Periodicity; Phenotype; Population; Positioning Attribute; Prognosis; Regulation; Resistance; Role; Structure; T-Lymphocyte; Testing; Therapeutic; Tumor stage; Tumor-associated macrophages; Tumor-infiltrating immune cells; Work; angiogenesis; base; cancer subtypes; chemotherapy; cytotoxic; cytotoxicity; drug-sensitive; experience; flexibility; immune checkpoint blockade; immunogenic; immunogenicity; in vivo; innovation; insight; macrophage; malignant breast neoplasm; mammary; novel; preference; protein expression; respiratory; success; therapeutic target; transplant model; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

Project Summary/Abstract Triple Negative Breast Cancer (TNBC) is a devastating disease with aggressive growth and frequent metastases. Less than 30% of patients with metastatic TNBC survive beyond five years after their diagnosis. While other breast cancer subtypes have well-defined endocrine markers, TNBC tumors lack such specific therapeutic targets, making cyclic chemotherapy the mainstay of treatment. Immune checkpoint blockade therapy aims to leverage TNBC’s inherent yet limited immunogenicity, though success has been restricted by other immunosuppressive elements in the tumor environment. The overarching goal is to find alternative and/or synergistic methods to enhance immune-mediated cytotoxicity in the TNBC tumor microenvironment. The overall objective of this proposal is to enhance tumor microenvironment immunogenicity by repolarizing macrophages out of a pro-tumor state and into a cytotoxic, anti-tumor state. The central hypothesis is that mitochondrial fusion governs tumor associated macrophages’ (TAM) pro-tumor functions within the tumor microenvironment. The rationale for this project is that macrophage metabolism defines polarization fate. Particularly, anti-tumor macrophages upregulate glycolysis while pro-tumor macrophages depend on oxidative phosphorylation. As mitochondria house oxidative phosphorylation-associated pathways, and as mitochondrial structure impacts oxidative phosphorylation efficiency, manipulating mitochondrial structure could determine polarization fate. This proposal consists of proof-of-principle studies to demonstrate macrophages are flexible and that repolarization can be achieved by manipulating mitochondrial structure in vitro and in vivo. Along this trajectory, the central hypothesis will be tested by pursuing two specific aims. Aim 1 will determine the role of mitochondrial dynamics in macrophage polarization. For this aim, we will culture TNBC tumor macrophages in vitro, manipulate mitochondrial dynamics, and then evaluate polarization. Aim 2 will determine whether TAM pro-tumor functions within the tumor microenvironment are dependent on mitochondrial fusion. In this aim, we will evaluate the effect of macrophages with altered mitochondrial dynamics on T cell cytotoxicity, metastasis, and angiogenesis. The proposed studies are innovative because they will evaluate direct causation between mitochondrial dynamics and macrophage polarization and will also define a relevant in vivo macrophage phenotype. The project is significant because it sets the foundation for manipulation of macrophage mitochondria as a therapeutic strategy to enhance tumor microenvironment immunogenicity for TNBC. Collectively, these studies will lend insight into the mechanisms that govern macrophage fate and make progress towards novel immune therapies for TNBC.

项目摘要/摘要 三重阴性乳腺癌（TNBC）是一种具有侵略性生长和经常转移的毁灭性疾病。 不到30％的转移性TNBC患者诊断出五年以上。而其他 乳腺癌亚型具有明确定义的内分泌标记，TNBC肿瘤缺乏这种特定的疗法 靶标，使环状化疗成为治疗的中流。免疫检查点封锁治疗的目的是 利用TNBC的继承但有限的免疫原性，尽管成功受到了其他的限制 肿瘤环境中的免疫抑制元素。总体目标是找到替代方案和/或 在TNBC肿瘤微环境中增强免疫介导的细胞毒性的协同方法。总体 该提议的目的是通过复制巨噬细胞来增强肿瘤微环境免疫原性 从肿瘤状态出现，进入细胞毒性，抗肿瘤状态。中心假设是线粒体融合 在肿瘤微环境中控制肿瘤相关的巨噬细胞（TAM）促肿瘤功能。这 该项目的理由是巨噬细胞代谢定义了极化命运。特别是抗肿瘤 巨噬细胞上调糖酵解，而促肿瘤巨噬细胞取决于氧化磷酸化。作为 线粒体室氧化磷酸化相关的途径，并随着线粒体结构的影响 氧化磷酸化效率，操纵线粒体结构可以确定极化命运。这 提案包括原则研究证明巨噬细胞的灵活性和复制 可以通过在体外和体内操纵线粒体结构来实现。沿着这一轨迹，中央 假设将通过追求两个具体目标来检验。 AIM 1将确定线粒体动力学的作用 在巨噬细胞极化中。为此，我们将体外培养TNBC肿瘤巨噬细胞，操纵 线粒体动力学，然后评估极化。 AIM 2将确定TAM Pro-Tumor是否功能 在肿瘤微环境中，取决于线粒体融合。在此目标中，我们将评估效果 巨噬细胞在T细胞细胞毒性，转移和血管生成方面有改变线粒体动力学的巨噬细胞。 拟议的研究具有创新性，因为它们将评估线粒体动力学之间的直接原因 和巨噬细胞极化，还将定义相关的体内巨噬细胞表型。该项目是 意义重大，因为它为巨噬细胞线粒体作为治疗策略奠定了基础 为了增强TNBC的肿瘤微环境免疫原性。这些研究共同洞察 控制巨噬细胞命运并取得新的TNBC免疫疗法的进展的机制。