Project 3: The Evolving Role of Regional Lymph Nodes in Melanoma Progression

项目3概要 癌症通常从其原发部位扩散并定植于区域淋巴结（LN），这代表了 进展的标志和分期的关键参数。淋巴结转移对预后的影响及应用 然而，微转移性LN疾病患者的完全LN剥离在实体瘤类型之间存在差异 和患者子集。根据定义，去除微转移性LN疾病的临床观察 提高生存率突出了我们对局部淋巴结转移理解的差距，并提出了质疑 顺序转移的简单模型。鉴于淋巴结既是早期转移部位， 器官，传播和免疫之间的相互作用可能是至关重要的理解如何LN的影响 结果。在这里，我们将研究肿瘤引流淋巴结的生物学，以询问区域引流淋巴结是否作为肿瘤的靶点。 一个教育网站，最终改变系统的宏观环境，有利于远处的肿瘤生长。 在这个建议中，我们测试的假设，前哨淋巴结经历了级联的细胞和分子的事件 使宿主易于接受肿瘤的发展为了验证这个假设，我们将建立一个无偏的， 时间和空间分辨地图区域排水LN。这将使我们能够识别临床相关的 通过整合对淋巴和LN的深入、机制性理解来确定结果的机制 生物学与高维成像和新的计算工具在小鼠和人类。建立 在这张地图上，我们将利用来自手术病例的新鲜冷冻淋巴结，存档的，FFPE匹配的原发和转移淋巴结， 和临床相关的小鼠模型，并确定支持肿瘤细胞接种的早期变化 并且黑素瘤细胞状态首先到达LN（Aim 1）。我们将进一步测试因果程序，包括类型 I干扰素信号传导，其可以在功能上启动这种肿瘤容许状态，并安装局部机制， 适应性免疫抑制，限制系统性免疫监视，从而限制远处转移（Aim 2）。 最后，我们将利用Core B的广泛资源和专业知识来研究免疫的效用 从存档的前哨LN组织中对患者风险进行分层的标志物，从而预测II期和III期的复发 黑色素瘤患者（Aim 3）。我们在这里提出的工作承诺将大大重新设想哨兵的作用 LN在系统性黑色素瘤进展中的作用这种概念上的转变可能会为管理当地的个性化策略提供信息。 疾病，从而动员抗肿瘤免疫和跨实体瘤类型的全身肿瘤控制， 识别基于免疫的LN特征，以分层黑色素瘤复发风险并指导临床护理。 通过该提案产生的资源和知识将通过NYULH公开提供 MetNet中心核心B和C，这将使这些观察扩展到其他实体瘤类型（例如， 乳腺癌）通过更广泛的转移研究网络，因此能够显着扩大 了解LN的转移和进展。

PROJECT 3 SUMMARY Cancers commonly spread from their primary site and colonize regional lymph nodes (LNs), representing a hallmark of progression and a key parameter for staging. The prognostic impact of LN metastasis and utility of complete LN dissection in patients with micrometastatic LN disease, however, varies between solid tumor types and patient subsets. The clinical observation that removal of micrometastatic LN disease does not by definition improve survival has highlighted a gap in our understanding of regional LN metastasis and calls into question the simple model of sequential metastasis. Given that LNs are both an early site of metastasis and immunological organs, the interplay between dissemination and immunity may be critical to understanding how LNs impact outcome. Here we will investigate the biology of tumor-draining LNs to ask whether regional draining LNs act as an educational site that ultimately shifts the systemic macroenvironment to favor distant tumor outgrowth. In this proposal we test the hypothesis that sentinel LNs undergo a cascade of cellular and molecular events that prime the host to be receptive to tumor progression. To test this hypothesis, we will build an unbiased, temporally, and spatially resolved map of regional draining LNs. This will enable us to identify clinically relevant mechanisms that determine outcome by integrating a deep, mechanistic understanding of lymphatic and LN biology together with high-dimensional imaging and novel, computational tools in mice and humans. To build this map, we will leverage fresh frozen LNs from surgical cases, archived, FFPE matched primary and metastasis pairs, and a clinically relevant mouse model, and determine the early changes that support tumor cell seeding and the melanoma cell states that first arrive in LNs (Aim 1). We will further test causal programs, including type I interferon signaling, that may functionally initiate this tumor permissive state and install local mechanisms of adaptive immune suppression that limit systemic immune surveillance and thereby distant metastasis (Aim 2). Finally, we will leverage the extensive resource and expertise of Core B to investigate the utility of immune markers to stratify patient risk from archived sentinel LN tissue and thereby predict recurrence in Stage II and III melanoma patients (Aim 3). The work we propose here promises to significantly reimagine the role of the sentinel LN in systemic melanoma progression. This conceptual shift may inform personalized strategies to manage local disease and thereby mobilize anti-tumor immunity and systemic tumor control across solid tumor types and identify immune-based LN features to stratify risk for recurrence in melanoma and guide clinical care. The resources and knowledge generated through this proposal will be made publicly accessible through NYULH MetNet Center Cores B and C, which will enable extension of these observations to other solid tumor types (e.g. breast cancer) through the broader Metastasis Research Network and therefore enable a significantly expanded understanding of LN metastasis and progression.