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
This project seeks to define the proteomic and cellular profiles of hemophagocytic lymphohistiocytosis associated with malignancies and describe the diversity within these patients. In so doing we intend to make the first data-driven descriptions of the pathogenesis of this fatal disorder and implicate future novel therapies.
