Redefining hemophagocytic lymphohistiocytosis in hematologic malignancies

噬血细胞性淋巴组织细胞增生症（HLH）是一种危及生命的炎症综合征， 在恶性肿瘤患者（M-HLH）中识别。然而，几乎所有早期已知的关于它的 病理生理学和治疗源自与家族性HLH（FHL）相关的临床和科学研究。 虽然FHL和M-HLH具有明显的临床相似性，但尚不清楚它们是否具有相似的病理生理学特征。 奥吉。事实上，即使M-HLH已经被认识了几十年，我们对它的病理几乎一无所知。 physiology.为了弥补这一差距，我们召集了一个国际合作者小组， 患者来源的样本，这将使我们能够比较血清蛋白质组学谱和免疫细胞表型， FHL、M-HLH、无并发症恶性肿瘤（U-M）和其他炎性疾病患者的类型 这些方法可能会对HLH产生广泛的新见解。基于M-之间明显的临床相似性， HLH和FHL，一些M-HLH患者可能与FHL非常相似，即使M-HLH患者 是多种多样的，足以涵盖多种不同的机制。因此，我们假设M-HLH是一个COM， 正性综合征包括：1.）其中恶性克隆基本上"模仿" FHL的患者; 2.）患者 与FHL相似的T细胞过度活化和"高干扰素血症"，以及; 3.）患者 与FHL不同，但尚不能分类（见图1）。 1）。此外，我们假设FHL样T细胞过度活化代表了一种新的副肿瘤免疫， 综合征，并可能定义受益于针对FHL开发的靶向抗IFN-γ治疗的患者， 以及抗癌免疫疗法，如免疫检查点抑制剂。 目标1.定义M-HLH中患者组的独特血清蛋白质组学谱。我们将雇用一名 稳健的蛋白质组学平台（SomaScan），用于评估M-HLH患者的样本，并与各组进行比较 上面列出的。我们将开发分类器来区分M-HLH和U-M，并在一个 探索性队列，并在验证队列中测试这些分类器的预测值。 目标二。定义M-HLH中"FHL样" T细胞活化谱的发生率。我们最近发现了一个 FHL中清晰的CD8 + T细胞谱，这很容易区分HLH与另一种高度炎症状态，细菌性 败血症我们将利用流式细胞术分析上述患者组的外周血T细胞谱， 集中在那些与FHL蛋白质组图谱最相似的人身上。我们还将比较T细胞和单核细胞基因 这些患者群体的表达谱。这些细胞研究将提供有价值的交叉验证， 补充上述蛋白质组学特征 1

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that is increasingly recognized in patients with malignancies (M-HLH). However, nearly early everything that is known about its pathophysiology and treatment is derived from clinical and scientific studies related to familial HLH (FHL). Though FHL and M-HLH have clear clinical similarities, it is not known whether they have similar pathophysiol- ogy. Indeed, even though M-HLH has been recognized for decades, we know nearly nothing about its patho- physiology. To remedy this gap, we have assembled an international group of collaborators and a unique set of patient-derived samples that will allow us to compare serum proteomic profiles and immune cellular pheno- types of patients with FHL, M-HLH, uncomplicated malignancies (U-M), and other inflammatory conditions in ways that are likely to yield broad new insights into HLH. Based on the clear clinical similarities between M- HLH and FHL, it is likely that some M-HLH patients will be quite similar to FHL, even though M-HLH patients are diverse enough to encompass multiple distinct mechanisms. Thus, we hypothesize that M-HLH is a com- posite syndrome, including: 1.) patients in which the malignant clone is essentially `mimicking' FHL; 2.) patients with T cell hyperactivation and `hyper-interferonemia' which is recognizably similar to FHL, and; 3.) patients with substantial innate immune dysregulation, which is dissimilar to FHL but not yet classifiable (see Figure 1). Furthermore, we hypothesize that FHL-like T cell hyperactivation represents a new paraneoplastic immune syndrome and may define patients who would benefit from targeted anti-IFN-g therapy developed for FHL, as well as anti-cancer immunotherapies, such as immune checkpoint inhibitors. Aim 1. Define the distinctive serum proteomic profiles of patient groups within M-HLH. We will employ a robust proteomic platform (SomaScan) to assess samples from patients with M-HLH, comparing to the groups listed above. We will develop classifiers to distinguish M-HLH from U-M and define M-HLH subgroups in an exploratory cohort and test the predictive value of these classifiers in a validation cohort. Aim 2. Define the incidence of `FHL-like' T cell activation profiles in M-HLH. We have recently identified a clear CD8+ T cell profile in FHL, which readily distinguishes HLH from another highly inflamed state, bacterial sepsis. We will utilize flow cytometry to analyze the peripheral blood T cell profiles of the patient groups above, focusing on those with proteomic profiles most similar to FHL. We will also compare T cell and monocyte gene expression profiles of these patient groups. These cellular studies will provide valuable cross-validation, com- plementing the proteomic characterization above 1