Epstein-Barr virus orchestrates spatial reorganization and immunomodulation in the classic Hodgkin lymphoma tumor microenvironment

Yao Yu Yeo; Huaying Qiu; Yunhao Bai; Bokai Zhu; Yuzhou Chang; Fabio Iannelli; Stephanie Pei Tung Yiu; Jason Yeung; Hendrik A Michel; Yuchen Wang; Yang Wang; Wenrui Wu; Kyle Wright; Muhammad Shaban; Sam Sadigh; Dingani Nkosi; Vignesh Shanmugam; Philip Rock; Precious Cramer; Julia Paczkowska; Pierre Stephan; Guanrui Liao; Amy Y Huang; Hongbo Wang; Han Chen; Leonie Frauenfeld; Louisa Kaufmann; Stefano Pileri; Bidisha Mitra; Benjamin E Gewurz; Bo Zhao; Garry P Nolan; Baochun Zhang; Alex K Shalek; Michael Angelo; Christian M Schürch; Faisal Mahmood; Roberto Chiarle; Qin Ma; W Richard Burack; Margaret A Shipp; Scott J Rodig; Sizun Jiang

doi:10.1016/j.xcrm.2026.102722

Epstein-Barr virus orchestrates spatial reorganization and immunomodulation in the classic Hodgkin lymphoma tumor microenvironment

Cell Rep Med. 2026 Apr 21;7(4):102722. doi: 10.1016/j.xcrm.2026.102722. Epub 2026 Mar 31.

Authors

Yao Yu Yeo¹, Huaying Qiu², Yunhao Bai³, Bokai Zhu⁴, Yuzhou Chang⁵, Fabio Iannelli⁶, Stephanie Pei Tung Yiu², Jason Yeung², Hendrik A Michel¹, Yuchen Wang², Yang Wang², Wenrui Wu², Kyle Wright⁷, Muhammad Shaban⁸, Sam Sadigh⁷, Dingani Nkosi⁹, Vignesh Shanmugam⁸, Philip Rock⁹, Precious Cramer², Julia Paczkowska¹⁰, Pierre Stephan¹¹, Guanrui Liao², Amy Y Huang⁷, Hongbo Wang¹², Han Chen¹³, Leonie Frauenfeld¹⁴, Louisa Kaufmann¹⁴, Stefano Pileri⁶, Bidisha Mitra¹², Benjamin E Gewurz¹⁵, Bo Zhao¹², Garry P Nolan¹³, Baochun Zhang¹⁰, Alex K Shalek¹⁶, Michael Angelo¹³, Christian M Schürch¹⁷, Faisal Mahmood⁸, Roberto Chiarle¹⁸, Qin Ma¹⁹, W Richard Burack⁹, Margaret A Shipp¹⁰, Scott J Rodig⁷, Sizun Jiang²⁰

Affiliations

¹ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
² Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
³ Department of Pathology, Stanford University, Stanford, CA, USA; Department of Chemistry, Stanford University, Stanford, CA, USA.
⁴ Department of Pathology, Stanford University, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
⁵ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA.
⁶ Division of Haematopathology, European Institute of Oncology IRCCS, Milan, Italy.
⁷ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁹ Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹¹ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Université de Paris, Assistance Publique-Hôpitaux de Paris, Hemato-oncologie, Saint-Louis Hôspital, Paris, France.
¹² Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹³ Department of Pathology, Stanford University, Stanford, CA, USA.
¹⁴ Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany.
¹⁵ Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA; Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶ Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁷ Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
¹⁸ Division of Haematopathology, European Institute of Oncology IRCCS, Milan, Italy; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA; Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA.
²⁰ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: sjiang3@bidmc.harvard.edu.

Abstract

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.

Keywords: EBV; Hodgkin lymphoma; multiplexed imaging; spatial proteomics; spatial transcriptomics; systems immunology; tumor microenvironment; tumor virus.

MeSH terms

CD8-Positive T-Lymphocytes / immunology
Epstein-Barr Virus Infections* / immunology
Epstein-Barr Virus Infections* / virology
Herpesvirus 4, Human* / immunology
Hodgkin Disease* / immunology
Hodgkin Disease* / pathology
Hodgkin Disease* / virology
Humans
Immunomodulation*
Reed-Sternberg Cells / immunology
Reed-Sternberg Cells / pathology
Tumor Microenvironment* / immunology
Viral Matrix Proteins / metabolism

Substances

Viral Matrix Proteins
EBV-associated membrane antigen, Epstein-Barr virus

Abstract

MeSH terms

Substances

Grants and funding