Metabolites regulating macrophage function in colorectal cancer

调节结直肠癌巨噬细胞功能的代谢物

• 批准号: 10727502
• 负责人: Subbaya Subramanian
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727502
• 关键词: Accounting; Affect; Aryl Hydrocarbon Receptor; Biological Assay; Cessation of life; Characteristics; Clinical; Coculture Techniques; Colon; Colorectal Cancer; Complex; Culture Media; Environment; Essential Amino Acids; Exposure to; Flow Cytometry; Homeostasis; Human; Immune; Immune checkpoint inhibitor; Immune response; In Vitro; Infiltration; Intervention; Investigation; Kynurenine; Macrophage; Malignant Neoplasms; Measures; Metabolic; Microsatellite Instability; Microsatellite Repeats; Modeling; Myeloid Cells; Normal tissue morphology; Organoids; Pathologic; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Phenylalanine; Pilot Projects; Prognostic Marker; Receptor Signaling; Regulation; Sampling; T cell infiltration; TNF gene; Tissues; Transforming Growth Factor beta; Tryptophan; Tumor Tissue; Undifferentiated; United States; anti-tumor immune response; cancer type; checkpoint therapy; colon cancer patients; cytokine; immune cell infiltrate; immunogenic; immunosuppressive macrophages; improved; insight; interest; metabolomics; microbial; microbiome; microbiota; monocyte; novel; pathogenic bacteria; patient population; screening; tumor; tumor microenvironment

ABSTRACT Most colorectal cancer (CRC) patients do not respond to immune checkpoint inhibitor therapies due to poor T cell infiltration and an immune suppressive environment. The pathological characteristics of CRC are unique due to the complex microbiome in the tumor microenvironment. Diverse bacterial species and metabolites in the tumor can alter the activity and function of infiltrating immune cells, regulating the tumor's immune environment. Therefore, understanding how tumor-enriched metabolites change the immune environment is crucial for developing novel microbiota/metabolite intervention approaches. We observed that macrophages resembling an M2-like phenotype are in a higher proportion in CRC samples compared to patient-matched normal tissues. Our metabolomic analysis of CRC tissues showed increases in essential amino acids, which strongly correlate with altered macrophage phenotype. Further, monocytes exposed to tumor-enriched metabolites such as tryptophan and phenylalanine increase markers associated with immunosuppressive macrophages. However, whether microbial-derived metabolites alter macrophage polarization and contribute to immunosuppressive phenotypes, which can influence the immune environment in CRC, remains unknown. We hypothesize that altered enrichment of metabolites in CRC correlates with immunosuppressive macrophages and that critical tumor-enriched metabolites modulate the macrophage phenotypes. In Aim 1, we will assess the impact of tumor-enriched metabolites on macrophage phenotype. In Aim 2, we will functionally validate key metabolites influencing macrophage polarization in CRC organoid coculture models. We will use a metabolite screening approach using human primary peripheral blood mononuclear cells from healthy donors and CRC patients to assess whether tumor-enriched metabolites can promote immunosuppressive macrophage phenotypes. In addition, we will use human microsatellite stable and microsatellite instable CRC organoids cocultured with patients matched undifferentiated monocytes and tumor- enriched metabolites to assess shifts in macrophage subtypes. We will identify critical metabolites that can alter macrophage phenotype and function, contributing to a sustained immunosuppressive tumor environment. Impact. Determining interactions between tumor-enriched metabolites and macrophage phenotype will increase the clinical implications of this study by solidifying the premise that the immune environment can be manipulated by endogenous metabolic regulation.

抽象的 大多数结直肠癌 (CRC) 患者由于 T 值较差而对免疫检查点抑制剂治疗没有反应 细胞浸润和免疫抑制环境。 CRC的病理特点具有独特性 肿瘤微环境中复杂的微生物组。不同的细菌种类和代谢物 肿瘤可以改变浸润免疫细胞的活性和功能，调节肿瘤的免疫环境。 因此，了解肿瘤富集的代谢物如何改变免疫环境对于治疗癌症至关重要。 开发新的微生物群/代谢物干预方法。 我们观察到类似 M2 样表型的巨噬细胞在 CRC 样本中所占比例较高 与患者匹配的正常组织进行比较。我们对结直肠癌组织的代谢组学分析显示， 必需氨基酸，与巨噬细胞表型的改变密切相关。此外，单核细胞 暴露于富含肿瘤的代谢物（例如色氨酸和苯丙氨酸）会增加与肿瘤相关的标记物 免疫抑制巨噬细胞。然而，微生物衍生的代谢物是否会改变巨噬细胞 极化并导致免疫抑制表型，从而影响免疫环境 CRC，仍然未知。我们假设 CRC 中代谢物富集的改变与 免疫抑制性巨噬细胞和关键的肿瘤富集代谢物调节巨噬细胞 表型。在目标 1 中，我们将评估肿瘤富集代谢物对巨噬细胞表型的影响。在 目标 2，我们将对影响 CRC 类器官中巨噬细胞极化的关键代谢物进行功能验证 共培养模型。 我们将使用来自人类原代外周血单核细胞的代谢物筛选方法 健康捐献者和结直肠癌患者评估富含肿瘤的代谢物是否可以促进 免疫抑制巨噬细胞表型。此外，我们将使用人类微卫星稳定和 微卫星不稳定的 CRC 类器官与患者匹配的未分化单核细胞和肿瘤细胞共培养 富集代谢物以评估巨噬细胞亚型的变化。我们将确定可以改变的关键代谢物 巨噬细胞表型和功能，有助于持续的免疫抑制肿瘤环境。 影响。确定肿瘤富集代谢物与巨噬细胞表型之间的相互作用将会增加 通过巩固免疫环境可以被操纵的前提，本研究的临床意义 通过内源性代谢调节。