Multidimensional Characterization of Tumor–Immune Architecture Reveals Clinically Relevant Classic Hodgkin Lymphoma Subtypes
The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve 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. Here, 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 crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.
Authors
- Shinya Rai (ORCID: https://orcid.org/0000-0003-3929-9751)
- Andrew Lytle (ORCID: https://orcid.org/0000-0002-9979-3690)
- Eric Lee (ORCID: https://orcid.org/0000-0003-2114-3118)
- Katsuyoshi Takata (ORCID: https://orcid.org/0000-0001-6890-1276)
- Mohammad Shahrokh Esfahani (ORCID: https://orcid.org/0000-0002-0950-3937)
- Laura K. Hilton (ORCID: https://orcid.org/0000-0002-6413-6586)
- Aixiang Jiang (ORCID: https://orcid.org/0000-0002-6153-7595)
- Stacy Hung
- David W. Scott (ORCID: https://orcid.org/0000-0002-0435-5947)
- Shaocheng Wu
- Michael Hong (ORCID: https://orcid.org/0000-0001-6638-6733)
- Claudia Cassidy
- Anca A. Prica (ORCID: https://orcid.org/0000-0001-5621-9261)
- Susana Ben‐Neriah (ORCID: https://orcid.org/0000-0002-2867-4037)
- Ali Sakhdari (ORCID: https://orcid.org/0000-0002-4610-7562)
- Juan Rangel Patiño
- Clémentine Sarkozy (ORCID: https://orcid.org/0000-0002-1942-9304)
- Talia Goodyear
- Adèle Telenius (ORCID: https://orcid.org/0000-0002-6901-5126)
- Michael Crump (ORCID: https://orcid.org/0000-0002-2230-8538)
- Celia Strong (ORCID: https://orcid.org/0000-0002-3374-7747)
- Andrew Roth (ORCID: https://orcid.org/0000-0003-3422-8823)
- Alexander M. Xu (ORCID: https://orcid.org/0000-0003-4877-4358)
- Stefan Alig (ORCID: https://orcid.org/0000-0001-6825-702X)
- Andrew P. Weng (ORCID: https://orcid.org/0000-0001-7394-5425)
- Makoto Kishida
- Ryan D. Morin (ORCID: https://orcid.org/0000-0003-2932-7800)
- Poul H. Sorensen (ORCID: https://orcid.org/0000-0001-7447-2199)
- Shannon Healy (ORCID: https://orcid.org/0000-0001-5463-6598)
- Merrill Boyle
- Gerben Duns (ORCID: https://orcid.org/0000-0001-8060-694X)
- Katy Milne (ORCID: https://orcid.org/0000-0001-8298-0142)
- Manabu Fujisawa (ORCID: https://orcid.org/0009-0007-1122-6549)
- Christian Steidl
- Denise Smorra
- Ash A Alizadeh
- Chantal Di Vito
- Cassandra Luksik
- Glenn Edin
- John Kuruvilla
- Robert Kridel
- Brad H. Nelson
- Michael Yu Li
- Akil Merchant
- Pedro Farinha
- Cecilia Lee
- Tomohiro Aoki
- Tomoko Miyata-Takata
- Yifan Yin
- Kerry J. Savage
- Laura Gonzalez
- Jasper CH. Wong
- Luke O`Brien
Institutions
- Cedars-Sinai Medical Center (US)
- BC Cancer Agency (CA)
- University Health Network (CA)
- University of British Columbia (CA)
- Simon Fraser University (CA)
- University of Limerick (IE)
- Princess Margaret Cancer Centre (CA)
- Park University (US)
- Stanford Medicine (US)
- University of Toyama (JP)
- Marie Curie (GB)
- University of Maryland, College Park (US)
- Institut Curie (FR)
- Stanford University (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-01-30
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-0859
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00