Distinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and few studies have comprehensively investigated the immune microenvironment and rare lymphocyte-predominant (LP) cells. Here we develop a NLPHL specific lymphocyte-predominant ecotype (LPE) model to identify 34 distinct cell states across 14 cell types that co-occur within 3 LPEs for 171 cases. LPE1 and LPE2 were characterized by immunosuppressive microenvironments with high expression of B2M on LP cells, CD8 T-cell exhaustion, immune checkpoint genes expressed by follicular T-cells, and an improved freedom from progression compared to LPE3 in training (n = 109, with 65% LPE1/2) and validation cohorts (n = 62, with 61% LPE1/2). We validate the co-occurrence and co-localization of cell states using spatial transcriptomics. Protein expression of HLA-I and HLA-II on LP cells and SSTR2 on dendritic cells was predictive of LPE1 (C-statistic=0.69), LPE2 (C-statistic=0.79), and LPE3 (C-statistic=0.60). This study establishes a clinically relevant biologic categorization for NLPHL.
Authors
- Maximilian Diehn (ORCID: https://orcid.org/0000-0003-2032-0581)
- Yasodha Natkunam (ORCID: https://orcid.org/0000-0002-9816-1018)
- Aaron M. Newman (ORCID: https://orcid.org/0000-0002-1857-8172)
- Francisco Vega (ORCID: https://orcid.org/0000-0001-5956-452X)
- Ash A. Alizadeh (ORCID: https://orcid.org/0000-0002-5153-5625)
- Pamela Allen
- Chelsea C. Pinnix (ORCID: https://orcid.org/0000-0003-3982-3664)
- Monica Palese (ORCID: https://orcid.org/0000-0002-2624-0868)
- Raphaël Steiner (ORCID: https://orcid.org/0000-0003-3717-3629)
- Vít Procházka (ORCID: https://orcid.org/0000-0002-9861-3117)
- Alice Šýkorová (ORCID: https://orcid.org/0000-0002-8773-6250)
- Timothy Flerlage
- Everett J. Moding (ORCID: https://orcid.org/0000-0001-7913-5351)
- Cristiane Milito (ORCID: https://orcid.org/0000-0002-2585-6636)
- Priyadarshini Kumar (ORCID: https://orcid.org/0000-0001-8945-6917)
- Jamie E. Flerlage (ORCID: https://orcid.org/0000-0002-4182-9355)
- Shengqin Su (ORCID: https://orcid.org/0000-0002-6946-8256)
- Lianna J. Marks (ORCID: https://orcid.org/0000-0001-6036-3127)
- Michael S. Binkley (ORCID: https://orcid.org/0000-0002-2640-5255)
- Robert B. West (ORCID: https://orcid.org/0000-0002-8330-8283)
- Ajay Subramanian (ORCID: https://orcid.org/0000-0001-7892-886X)
- Troy Noordenbos (ORCID: https://orcid.org/0000-0003-0583-4584)
- Darina Paulino
- Ranjana H. Advani (ORCID: https://orcid.org/0000-0002-3219-2292)
- Chunfang Zhu (ORCID: https://orcid.org/0000-0002-6773-0820)
- Stefan Alig (ORCID: https://orcid.org/0000-0001-6825-702X)
- Richard T. Hoppe (ORCID: https://orcid.org/0000-0003-0125-0194)
- Joseph G. Schroers‐Martin (ORCID: https://orcid.org/0000-0003-4128-2537)
- Heidi Móciková (ORCID: https://orcid.org/0000-0003-2034-0769)
- Shuchun Zhao (ORCID: https://orcid.org/0000-0003-0462-768X)
- Anusha Kalbasi (ORCID: https://orcid.org/0000-0001-8692-1457)
- Sheren F Younes (ORCID: https://orcid.org/0000-0002-8961-3043)
- Natalie J. Park
- Alan Ramsay
Institutions
- Universidade Federal do Rio de Janeiro (BR)
- St. Jude Children's Research Hospital (US)
- University College London Hospitals NHS Foundation Trust (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Emory University (US)
- Piedmont Cancer Institute (US)
- University Hospital Olomouc (CZ)
- Stanford Medicine (US)
- University Hospital Hradec Králové (CZ)
- University Hospital Kralovske Vinohrady (CZ)
- University College London (GB)
- University of Rochester (US)
- Palacký University Olomouc (CZ)
- Universidade Federal do Estado do Rio de Janeiro (BR)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1038/s41467-025-63339-9
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministerstvo Zdravotnictví Ceské Republiky
- Servier
- National Cancer Institute