Characterizing the immune and metabolic profiles of cutaneous T-cell lymphoma in formalin-fixed paraffin-embedded skin tissue samples

表征福尔马林固定石蜡包埋皮肤组织样本中皮肤 T 细胞淋巴瘤的免疫和代谢特征

• 批准号: 10058252
• 负责人: Darci Phillips
• 金额: $ 3.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058252
• 关键词: Address; Antibodies; Benign; Blood; Cell Communication; Cell Line; Cell physiology; Cells; Clinical; Complex; Coupled; Cutaneous T-cell lymphoma; Data; Data Set; Dendritic Cells; Detection; Diagnosis; Diagnostic; Disease; Early Diagnosis; Energy Metabolism; Formalin; Glucose; Glycolysis; Goals; Growth Factor; Heterogeneity; Histologic; Image; Immune; Immune mediated destruction; Immunity; Immunohistochemistry; Immunomodulators; Individual; Light; Machine Learning; Malignant - descriptor; Malignant Neoplasms; Metabolic; Metabolism; Metals; Molecular; Morphology; Multiparametric Analysis; Multiplexed Ion Beam Imaging; Non-Malignant; Outcome; Paraffin Embedding; Pathogenesis; Patients; Phenotype; Play; Prognostic Marker; Regulatory T-Lymphocyte; Reporting; Research; Resolution; Role; Sampling; Sirolimus; Skin; Skin Tissue; Slide; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrometry, Mass, Secondary Ion; Systemic Therapy; T-Lymphocyte; Techniques; Technology; Therapeutic; Tissue Embedding; Tissue Sample; Treatment outcome; Tumor Suppression; Work; antibody conjugate; diagnostic biomarker; effector T cell; fatty acid oxidation; improved; innovation; insight; mTOR Inhibitor; machine learning algorithm; macrophage; metabolic profile; metabolomics; molecular diagnostics; nanometer resolution; neoplastic cell; new technology; prognostic; protein expression; skin lesion; therapeutic biomarker; therapeutic target; treatment response; treatment strategy; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Cutaneous T-cell lymphoma (CTCL) is a rare, but potentially devastating malignancy of the skin. Early detection of CTCL is associated with positive clinical outcomes, but diagnosis is often complicated by the heterogeneous clinical and histological presentation. Additionally, systemic therapies remain sub- optimal for CTCL, highlighting the need for new treatment strategies. To date, most studies have been performed on blood from CTCL patients, which has revealed a complex interplay between host immunity, malignant T-cells and the tumor microenvironment. However, the molecular mechanisms that govern disease pathogenesis, especially in the skin, remain largely undefined. The goal of the proposed research is to use new technologies that allow for multi-parametric, high- resolution analyses in formalin-fixed paraffin-embedded (FFPE) skin tissue samples to define the immune and metabolic profiles of CTCL at different stages of disease. The first technology is Multiplexed Ion Beam Imaging (MIBI), which uses secondary ion mass spectrometry to visualize up to 100 metal conjugated antibodies simultaneously at nanometer resolution in FFPE tissue sections. Specifically, Aim I will use MIBI to define the heterogeneity and plasticity of cells that exist at the CTCL tumor-host interface, to improve the precision with which CTCL is diagnosed and treated. The second technology is matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), which can detect thousands of metabolites in FFPE tissue sections. Specifically, Aim II will use MALDI-MSI to determine the reflective metabolic activity of the CTCL microenvironment, thereby adding functional insight to disease pathogenesis and revealing potential metabolically active therapeutic targets. Overall, these studies will characterize the molecular heterogeneity and functional complexity of CTCL, which will shed light on how this disease evades immune destruction and reprograms energy- metabolism. As such, this work promises to improve the detection, treatment and clinical outcomes for CTCL.

项目概要/摘要 皮肤 T 细胞淋巴瘤 (CTCL) 是一种罕见但具有潜在破坏性的皮肤恶性肿瘤。 CTCL 的早期发现与积极的临床结果相关，但诊断通常很复杂 异质的临床和组织学表现。此外，全身治疗仍处于亚健康状态。 CTCL 的最佳选择，强调需要新的治疗策略。迄今为止，大多数研究已 对 CTCL 患者的血液进行的研究揭示了宿主免疫之间复杂的相互作用， 恶性T细胞和肿瘤微环境。然而，控制的分子机制 疾病的发病机制，尤其是皮肤疾病的发病机制，在很大程度上仍不明确。 拟议研究的目标是使用允许多参数、高 对福尔马林固定石蜡包埋 (FFPE) 皮肤组织样本进行分辨率分析，以确定免疫 以及 CTCL 在疾病不同阶段的代谢特征。第一项技术是多重离子束 成像 (MIBI)，使用二次离子质谱法可视化多达 100 个金属共轭体 在 FFPE 组织切片中同时以纳米分辨率检测抗体。具体来说，我将使用目标 MIBI 定义 CTCL 肿瘤-宿主界面上存在的细胞的异质性和可塑性， 提高CTCL诊断和治疗的精确度。第二种技术是矩阵辅助 激光解吸/电离质谱成像 (MALDI-MSI)，可检测数千个 FFPE 组织切片中的代谢物。具体来说，Aim II 将使用 MALDI-MSI 来确定反射 CTCL 微环境的代谢活动，从而增加对疾病的功能洞察 发病机制并揭示潜在的代谢活性治疗靶点。 总的来说，这些研究将表征分子异质性和功能复杂性 CTCL，这将揭示这种疾病如何逃避免疫破坏并重新编程能量- 代谢。因此，这项工作有望改善以下疾病的检测、治疗和临床结果： CTCL。