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

项目摘要/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。 早期发现CTCL与阳性的临床结果相关，但诊断通常很复杂。 由不同的临床和组织学表现。此外，系统性治疗仍处于次要地位 对于四氯化碳来说是最好的，强调了需要新的治疗策略。到目前为止，大多数研究都是 对CTCL患者的血液进行了检测，这揭示了宿主免疫之间复杂的相互作用， 恶性T细胞与肿瘤微环境。然而，支配人类的分子机制 疾病的发病机制，特别是皮肤的发病机制，在很大程度上仍然不清楚。 拟议研究的目标是使用新技术，允许多参数、高性能 福尔马林固定石蜡包埋(FFPE)皮肤组织样品的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。第一项技术是多路离子束 成像(MIBI)，它使用二次离子质谱学来可视化多达100个金属共轭 在FFPE组织切片中以纳米分辨率同时检测抗体。具体地说，我将使用Aim MIBI定义存在于CTCL肿瘤-宿主界面的细胞的异质性和可塑性，以 提高CTCL诊断和治疗的精确度。第二种技术是矩阵辅助技术。 激光解吸/电离质谱学成像(MALDI-MSI)，可以检测数千种 FFPE组织切片中的代谢产物。具体来说，AIM II将使用MALDI-MSI来确定反射 CTCL微环境的代谢活性，从而增加对疾病的功能洞察力 发病机制和揭示潜在的代谢活性治疗靶点。 总体而言，这些研究将表征分子的异质性和功能的复杂性 CTCL，这将揭示这种疾病是如何逃避免疫破坏和重新编程能量的- 新陈代谢。因此，这项工作有望改善对脑膜瘤的检测、治疗和临床结果。 CTCL。

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.