Redefining hemophagocytic lymphohistiocytosis in hematologic malignancies

噬血细胞性淋巴组织细胞增多症是一种威胁生命的炎症性综合征，其发病率越来越高。 在恶性肿瘤患者中被识别(M-HLH)。然而，几乎在早期，关于它的一切已知的 病理生理学和治疗源于与家族性HLH(FHL)相关的临床和科学研究。 虽然FHL和M-HLH有明显的临床相似之处，但尚不清楚它们是否具有相似的病理生理学。 奥奇。事实上，尽管M-HLH已经被认识了几十年，但我们对它的病理性几乎一无所知- 生理学。为了弥补这一差距，我们召集了一个国际合作者小组和一套独特的 患者来源的样本，将使我们能够比较血清蛋白质组图谱和免疫细胞表型 患有FHL、M-HLH、无并发症的恶性肿瘤(U-M)和其他炎症性疾病的患者类型 这些方法可能会对HLH产生更广泛的新见解。基于明显的临床相似之处，M- HLH和FHL，很可能一些M-HLH患者会非常类似于FHL，即使M-HLH患者 具有足够的多样性，可以包含多种不同的机制。因此，我们假设M-HLH是一个COM-HLH。 复合综合征，包括：1)恶性克隆基本上是“模仿”FHL的患者；病人 T细胞过度活化和类似于FHL的高干扰素血症，以及；病人 患有严重的先天性免疫失调，与FHL不同，但尚不能分类(见图 1)。此外，我们假设FHL样T细胞过度激活代表了一种新的副肿瘤免疫 综合征，并可能定义哪些患者将受益于为FHL开发的靶向抗干扰素-g治疗，如 以及抗癌免疫疗法，如免疫检查点抑制剂。 目的1.明确M-HLH患者组的独特血清蛋白质组学特征。我们将聘请一名 强大的蛋白质组平台(SomaScan)用于评估M-HLH患者的样本，与这些组相比 上面列出了。我们将开发分类器来区分M-HLH和U-M，并定义M-HLH子群 探索性队列，并在验证队列中测试这些分类器的预测价值。 目的2.明确“类FHL”T细胞在M-HLH中的发生率。我们最近发现了一种 FHL中清晰的CD8+T细胞特征，这很容易将HLH与另一种高度炎症状态细菌区分开来 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细胞图谱， 重点研究那些蛋白质组图谱与FHL最相似的基因。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，COM- 实现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