Multidimensional Characterization of Tumor–Immune Architecture Reveals Clinically Relevant Classic Hodgkin Lymphoma Subtypes

作者：Tomohiro Aoki, Gerben Duns, Shinya Rai, Aixiang Jiang, Andrew Lytle, Yifan Yin, Makoto Kishida, Michael Yu Li, Cecilia Lee, Denise Smorra, Laura K. Hilton, Shannon Healy, Stefan Alig, Mohammad Shahrokh Esfahani, Clémentine Sarkozy, Stacy Hung, Katy Milne, Adèle Telenius, Luke O’Brien, Jasper C. H. Wong, Claudia Cassidy, Manabu Fujisawa, Celia Strong, Talia Goodyear, Chantal Di Vito, Cassandra Luksik, Glenn Edin, Laura Gonzalez, Juan Rangel Patiño, Michael Hong, Shaocheng Wu, Eric Lee, Ali Sakhdari, Katsuyoshi Takata, Tomoko Miyata-Takata, Merrill Boyle, Susana Ben‐Neriah, Andrew P. Weng, Alexander M. Xu, Akil Merchant, Andrew Roth, Michael Crump, John Kuruvilla, Anca Prica, Robert Kridel, David G. Huntsman, Brad H. Nelson, Pedro Farinha, Ryan D. Morin, Ash A Alizadeh, Kerry J. Savage, David W. Scott, Christian Steidl · 发表于：Cancer Discovery · 年份：2026 · DOI：10.1158/2159-8290.cd-25-0859 · 被引用次数：3 · 研究领域：Lymphoma Diagnosis and Treatment、Single-cell and spatial transcriptomics、Cancer Immunotherapy and Biomarkers

The tissue architecture of classic Hodgkin lymphoma (cHL) is unique among cancers and is characterized by rare malignant Hodgkin and Reed-Sternberg cells that coevolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. In this study, we employed an integrative, multimodal approach to characterize cHL tumors using malignant cell sequencing, spatial transcriptomics, and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME cross-talk. These findings highlight the significance of multidimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities. SIGNIFICANCE: Our systematic and comprehensive genomic and spatially resolved profiling of Hodgkin lymphoma revealed a paradigmatic link between a genetic disease subtype and TME composition and function. Insights into mutation-driven mechanisms of deregulated cytokine signaling will pave the way for therapeutic interven...