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Abstract

Mediastinal B-cell lymphomas are lymphoid malignancies that arise in or primarily involve the mediastinum, most prominently primary mediastinal large B-cell lymphoma (PMBCL) and a subset of classical Hodgkin lymphoma (CHL). These entities share overlapping genetic and transcriptional features and are thought to represent a biological continuum originating in the anterior mediastinum. Despite extensive molecular characterization of malignant cells, the role of tissue context and cell–cell interactions in shaping disease phenotype, progression, and relapse remains poorly understood. The overarching goal of this thesis is to define how tissue-specific immune ecosystems influence the biology of mediastinal lymphomas. Using an integrated framework combining imaging mass cytometry (IMC), single-cell RNA sequencing (scRNA-seq), single-cell BCR sequencing and single cell multiomic profiling, this work demonstrates that mediastinal lymphomas are best understood as ecosystem-driven malignancies. In diagnostic CHL, high-dimensional spatial profiling reveals reproducible and genetically linked tumor microenvironment architectures. Genetically defined subgroups of CHL are associated with distinct spatial ecosystem states, indicating that malignant cell genotype is translated into tissue-level immune organization rather than acting independently of the microenvironment. Extending this framework to CHL reveals that relapsed disease represents a biologically distinct ecosystem state rather than simple persistence of diagnostic disease. Single-cell and spatial analyses identify an underappreciated role for non-malignant B cells, demonstrating enrichment of Galectin-9+ naïve B cells in early-relapse CHL and their spatial association with immunosuppressive T-cell populations. These findings highlight immune microenvironment remodeling as a critical feature of relapse biology. Finally, multiomic and spatial characterization of human thymic B cells provides insight into the tissue-restricted biology of PMBCL. This work supports a model in which PMBCL arises from thymus-imprinted B-cell states shaped by local immune regulation rather than classical germinal center differentiation. Together, this thesis establishes a unified ecosystem-based framework for understanding mediastinal lymphomas, emphasizing that malignant evolution, immune regulation, and clinical behavior emerge from coordinated interactions within specific tissue contexts. These findings have implications for biomarker development and for therapeutic strategies that target both malignant cells and the immune ecosystems that sustain them.