Quantitative assessment of pre-metastatic immune subversion as a risk factor for melanoma relapse

转移前免疫颠覆作为黑色素瘤复发危险因素的定量评估

• 批准号: 10683924
• 负责人: SVETOMIR Nenad MARKOVIC
• 金额: $ 61.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683924
• 关键词: Address; Adjuvant; Adjuvant Therapy; Advanced Malignant Neoplasm; Algorithms; Biological; Biological Markers; Biopsy; Cancer Relapse; Cause of Death; Cells; Chronic; Climate; Clinical; Complement; Cutaneous Melanoma; Data; Detection; Development; Diagnosis; Disabled Persons; Disease; Down-Regulation; Early Intervention; Excision; Excision biopsy; Fostering; Goals; Human; Image; Immune; Immune System Diseases; Immune response; Immunologic Surveillance; Immunologics; Immunosuppression; Immunotherapy; In Vitro; Intercellular Fluid; Intervention; Knowledge; Laboratories; Liquid substance; Location; Lymph; Lymph Node Dissections; Lymphatic; Lymphatic System; Machine Learning; Malignant Neoplasms; Mediating; Mediator; Melanoma Cell; Metastatic Melanoma; Metastatic Neoplasm to Lymph Nodes; Microanatomy; Micrometastasis; Modeling; National Comprehensive Cancer Network; Natural History; Neoplasm Metastasis; Operative Surgical Procedures; Pathologic; Patient risk; Patients; Pattern; Primary Neoplasm; Process; Prognosis; Prognostic Factor; Recommendation; Recurrence; Recurrent Malignant Neoplasm; Relapse; Risk; Risk Assessment; Risk Factors; S100A9 gene; Sentinel Lymph Node; Series; Signal Transduction; Site; Solid; Solid Neoplasm; Surveys; Systemic Therapy; Testing; Therapeutic; Tissues; Translating; Tumor-Associated Process; Tumor-Derived; Work; cancer cell; cancer recurrence; carcinogenesis; clinical risk; clinically relevant; digital; draining lymph node; extracellular vesicles; follow-up; imaging approach; imaging biomarker; imaging modality; immune function; immunoregulation; improved; innovation; insight; lymph nodes; lymphatic circulation; lymphatic vessel; melanoma; multiplexed imaging; neoplastic cell; novel; patient stratification; predictive tools; preservation; prognostic; prognostic signature; prognostic tool; prognostic value; radiological imaging; relapse risk; risk prediction; risk stratification; therapeutic target; tool; tumor; tumor microenvironment; virtual

PROJECT SUMMARY/ABSTRACT There is a fundamental gap in understanding the immunological paradox by which solid tumors first metastasize via lymphatic channels into the immune-rich lymph node. During this process, immune surveillance is disabled, ultimately allowing metastatic dissemination to the precise location where it should be first eliminated—the tumor-draining, sentinel lymph node (SLN). While notably prognostic, it is clear the metastatic status of the SLN alone is not sufficient in determining patient’s risk or relapse. Therefore, understanding the mechanisms underlining this chronic process of tumor mediated regional immunosuppression, commonly referred to as pre-metastatic niche (PMN) formation in the SLN will lend significant insights for developing improved prognostic and therapeutic tools to detect and reverse cancer dissemination early in the natural history of metastatic progression. Our long term goal is to develop therapeutic strategies capable of overcoming the immune compromise of the SLN PMN and thereby disrupt the first stage of cancer metastasis. Therefore, the objective of the current work is to mechanistically interrogate the process by which the subcellular component of the primary tumor lymphatic effluent directly mediates PMN formation. The central hypothesis proposes that in solid tumors, subcellular mediators derived from the primary tumor microenvironment actively traffic through the lymphatics and in a cargo-dependent manner create a PMN in the tumor-draining SLN. This hypothesis has been formulated on the basis of preliminary data produced in the applicant’s laboratory; namely the discovery and characterization of human lymphatic extracellular vesicles (L-EV) which have a demonstrated capacity to modulate immune function. The rationale asserts that in elucidating the factors and signatures that define PMN formation in the SLN, the knowledge gained will be significant as it will identify histopathologic biomarkers that could aid in patient risk stratification beyond the presence of melanoma cells in the SLN. Guided by strong preliminary data, this hypothesis will be tested in two specific aims: 1) identify mechanisms whereby lymphatic subcellular factors promote immune dysfunction in the pre-metastatic SLN beyond those already identified (i.e. S100A9); 2) evaluate the prognostic utility of these immune-modulating factors in predicting risk of recurrence by considering the comprehensive, interactive cellular landscape that defines the immunologically compromised SLN. The approach is innovative as it will use a mechanism-driven model to identify subcellular factors from a previously uncharacterized biological fluid, human lymph (Aim 1), complemented by a novel, multiplexed biomarker imaging approach in order to survey the SLN immunological landscape in a quantitative and spatially preserved manner to ultimately translate predictive features into clinically amenable platforms (Aim 2). Such findings will result in a refined definition of early-stage patients at risk of relapse and in need of earlier interventions.

项目概要/摘要 对于实体瘤首先产生的免疫学悖论的理解存在根本性的差距 通过淋巴通道转移到免疫丰富的淋巴结，在此过程中，免疫。 监视被禁用，最终导致转移性传播到其应有的精确位置 首先消除的是肿瘤引流前哨淋巴结（SLN），虽然预后显着，但很明显。 仅前哨淋巴结的转移状态不足以确定患者的风险或复发。 了解肿瘤介导的区域性慢性过程的潜在机制 免疫抑制，通常称为 SLN 中的转移前生态位 (PMN) 形成，将有助于 对改进预后和治疗工具以检测和逆转癌症的重要见解 我们的长期目标是发展转移进展自然史的早期传播。 能够克服 SLN PMN 免疫损害并由此破坏的治疗策略 因此，当前工作的目标是机械地转移。 直接询问原发性肿瘤淋巴流出物的亚细胞成分的过程 介导 PMN 形成的中心假设提出，在实体瘤中，亚细胞介质衍生。 来自原发性肿瘤微环境的细胞活跃地通过淋巴管并以货物依赖的方式运输 方式在肿瘤引流前哨淋巴结中创建 PMN 这一假设是在以下基础上提出的。 申请人实验室产生的初步数据；即发现和表征 人类淋巴细胞外囊泡 (L-EV) 具有调节能力 其基本原理是阐明定义 PMN 的因素和特征。 SLN 中的形成，获得的知识将非常重要，因为它将识别组织病理学生物标志物 可以帮助患者在前哨淋巴结中存在黑色素瘤细胞的情况下进行风险分层。 根据初步数据，该假设将在两个具体目标上进行检验：1）确定淋巴管的机制 亚细胞因子促进转移前 SLN 中的免疫功能障碍，超出了已经确定的范围（即， S100A9)；2) 评估这些免疫调节因素在预测复发风险中的预后效用 通过考虑定义免疫学的全面的、交互式的细胞景观 该方法是创新的，因为它将使用机制驱动的模型来识别亚细胞。 来自以前未表征的生物液体——人体淋巴液（目标 1）的因子，辅以一种新颖的、 多重生物标志物成像方法，以定量调查 SLN 免疫学景观 和空间保留的方式最终将预测特征转化为临床上适用的平台 （目标 2）这些发现将导致对有复发风险和需要治疗的早期患者的精确定义。 早期干预。