[F31] Immunobiology of malignancy-associated hemophagocytic lymphohistiocytosis

Description

Project Summary Malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) is a lethal cytokine storm syndrome associated with a high fatality rate in patients with hematologic cancers. Despite its severity, the tissue-level immunobiology of M-HLH remains undefined. Current human studies have been limited to serum biomarker analysis, epidemiology, and predictive indices, which fail to reveal the cellular sources or local dynamics of inflammation. Therefore, there is a critical need for direct studies of tissue-level immune perturbations to identify actionable targets. We propose to study a unique set of bone marrow biopsies from patients with M- HLH obtained during active disease flares using high-dimensional spatial multi-omics. In preliminary whole- transcriptome spatial profiling, we identified a profoundly inflamed marrow microenvironment characterized by high type I and II interferon activity and T cell exhaustion. Crucially, we observed that interferon gamma (IFNγ) correlated strongly with CD8+ T cell and macrophage markers in specific tissue regions. We therefore hypothesize that M-HLH is defined by spatially restricted CD8+ T cell-macrophage niches in the marrow that sustain pathological IFNγ signaling, amplified by inflammatory interactions with malignant cells. In Aim 1, we will define the spatial niches of inflammation in an expanded cohort of M-HLH patients (n=18) using unbiased, whole-transcriptome spatial profiling (GeoMx DSP). This will establish the spatial compartmentalization of the "storm" and identify the specific signaling pathways active within these foci. In Aim 2, we will define the cellular basis of these niches. We will map the specific ligand-receptor interactions between immune and tumor cells using spatial single-cell transcriptomic profiling (CosMx SMI) and establish a causal link by modeling key T cell-macrophage interactions (IL-12, IL-15, MHC-I) in a tractable in vitro system. The proposed research will result in the first detailed human study of the spatial mechanisms underlying M-HLH. This proposal will be completed in Dr. Carl June’s laboratory with a robust mentorship team harboring diverse expertise in spatial biology and immunology. Rigorous research training, clinical immersion, and scientific opportunities will further prepare the candidate for a career as an independent physician-scientist. Istituzione: UNIVERSITY OF PENNSYLVANIA PI: Samuel Kim Progetto: 1F31CA317809-01

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Source: reporter.nih.gov