Epstein-Barr virus orchestrates spatial reorganization and immunomodulation in the classic Hodgkin lymphoma tumor microenvironment
Classic Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells within a T-cell-rich tumor microenvironment (TME). Epstein-Barr virus (EBV) is present in ∼25% of cases, but its contribution to pathogenesis and immunomodulation remains unclear due to technical barriers. Using complementary spatial proteomics and transcriptomics across multi-institutional cohorts, we systematically map key EBV-linked TME reorganization. EBV-positive cHL exhibits distinct immunological features, including memory CD8 T cell enrichment, heightened T cell dysfunction spatially correlated with HRS proximity, and terminally exhausted T cell signatures contrasting with progenitor-exhausted patterns in EBV-negative disease. We identify EBV-encoded LMP1 as a factor in T cell dysfunction through enhanced HRS:CD8 interactions, and its expression level correlates with T cell terminal exhaustion in a distance-dependent manner. This spatial framework dissects viral-mediated immune evasion in the cHL TME, highlighting potential therapeutic opportunities to target virus-associated T cell dysfunction for precision immunotherapy in virus-associated malignancies.
Authors
- S. Brian Jiang
- Bokai Zhu (ORCID: https://orcid.org/0000-0003-3599-9419)
- Mohammed Shaban (ORCID: https://orcid.org/0000-0001-7792-0946)
- Leonie Frauenfeld (ORCID: https://orcid.org/0000-0003-4236-5799)
- Roberto Chiarle (ORCID: https://orcid.org/0000-0003-1564-8531)
- K A Wright
- Christian M. Schürch (ORCID: https://orcid.org/0000-0002-1792-1768)
- M A Shipp
- Pierre Stéphan (ORCID: https://orcid.org/0000-0001-5999-284X)
- Fabio Iannelli (ORCID: https://orcid.org/0000-0002-2777-1417)
- Dingani Nkosi (ORCID: https://orcid.org/0000-0002-3946-3016)
- Garry P. Nolan (ORCID: https://orcid.org/0000-0002-8862-9043)
- Bidisha Mitra
- Philip Rock (ORCID: https://orcid.org/0000-0003-0031-6032)
- Hendrik A. Michel (ORCID: https://orcid.org/0000-0001-7025-5605)
- Scott J. Rodig (ORCID: https://orcid.org/0000-0003-1761-9769)
- Sam Sadigh (ORCID: https://orcid.org/0000-0003-2557-7415)
- Julia Paczkowska (ORCID: https://orcid.org/0000-0002-3976-4353)
- Benjamin E. Gewurz (ORCID: https://orcid.org/0000-0002-3965-3418)
- Baochun Zhang (ORCID: https://orcid.org/0000-0003-1759-1161)
- Faisal Mahmood (ORCID: https://orcid.org/0000-0001-7587-1562)
- Yao Yu Yeo (ORCID: https://orcid.org/0000-0002-7604-2296)
- Guanrui Liao
- Stephanie Pei Tung Yiu (ORCID: https://orcid.org/0000-0002-1792-247X)
- Yuchen Wang (ORCID: https://orcid.org/0000-0001-8706-9016)
- Bing Zhao (ORCID: https://orcid.org/0000-0001-5999-9240)
- Yuzhou Chang (ORCID: https://orcid.org/0000-0003-2198-3491)
- An Huang (ORCID: https://orcid.org/0000-0002-4378-8841)
- Huaying Qiu
- Vignesh Shanmugam
- Michael Angelo
- Precious Cramer
- Louisa Kaufmann
- Stefano Pileri
- Hongbo Wang
- Yang Wang
- Han Chen
- W. Richard Burack
- Jason Yeung
- Qin Ma
- Alex K. Shalek
- Wenrui Wu
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- University of Rochester Medical Center (US)
- Dana-Farber Cancer Institute (US)
- University Children's Hospital Tübingen (DE)
- The Ohio State University (US)
- University of Turin (IT)
- European Institute of Oncology (IT)
- Stanford University (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1016/j.xcrm.2026.102722
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bill and Melinda Gates Foundation
- Gilead Sciences
- Broad Institute
- National Institutes of Health