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: 10547765
• 负责人: Hilda Lyn Chan
• 金额: $ 5.27万
• 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/10547765
• 关键词: Adopted; Aerobic; Anti-Inflammatory Agents; Cancer Etiology; Cancer Prognosis; Categories; Cell physiology; Cessation of life; Characteristics; Classification; 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; Macrophage; 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; breast cancer survival; cancer subtypes; chemotherapy; cytotoxic; cytotoxicity; drug-sensitive; experience; flexibility; immune cell infiltrate; immune checkpoint blockade; immunogenic; immunogenicity; in vivo; innovation; insight; malignant breast neoplasm; mammary; novel; preference; programs; 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.

项目概要/摘要 三阴性乳腺癌（TNBC）是一种具有侵袭性生长和频繁转移的毁灭性疾病。 不到 30% 的转移性 TNBC 患者在诊断后存活超过五年。而其他 乳腺癌亚型具有明确的内分泌标志物，TNBC 肿瘤缺乏此类特异性治疗 目标，使循环化疗成为主要的治疗方法。免疫检查点阻断疗法的目的是 利用 TNBC 固有但有限的免疫原性，尽管成功受到其他因素的限制 肿瘤环境中的免疫抑制成分。总体目标是寻找替代方案和/或 增强 TNBC 肿瘤微环境中免疫介导的细胞毒性的协同方法。整体 该提案的目的是通过复极化巨噬细胞来增强肿瘤微环境的免疫原性 脱离促肿瘤状态并进入细胞毒性、抗肿瘤状态。中心假设是线粒体融合 控制肿瘤微环境中肿瘤相关巨噬细胞（TAM）的促肿瘤功能。这 该项目的基本原理是巨噬细胞代谢决定极化命运。特别是抗肿瘤 巨噬细胞上调糖酵解，而促肿瘤巨噬细胞则依赖于氧化磷酸化。作为 线粒体包含氧化磷酸化相关途径，并且线粒体结构影响 氧化磷酸化效率，操纵线粒体结构可以决定极化命运。这 该提案包括原理验证研究，以证明巨噬细胞是灵活的并且复极化 可以通过在体外和体内操纵线粒体结构来实现。沿着这个轨迹，中央 假设将通过追求两个具体目标来检验。目标 1 将确定线粒体动力学的作用 在巨噬细胞极化中。为此，我们将在体外培养TNBC肿瘤巨噬细胞，操纵 线粒体动力学，然后评估极化。目标 2 将确定 TAM 是否具有促肿瘤功能 肿瘤微环境内的变化依赖于线粒体融合。为了这个目标，我们将评估效果 线粒体动力学改变的巨噬细胞对 T 细胞的细胞毒性、转移和血管生成的影响。这 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因果关系 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，因为它为操纵巨噬细胞线粒体作为治疗策略奠定了基础 增强TNBC的肿瘤微环境免疫原性。总的来说，这些研究将有助于深入了解 控制巨噬细胞命运的机制并在 TNBC 的新型免疫疗法方面取得进展。