Distinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma

Ajay Subramanian; Shengqin Su; Jamie Flerlage; Stefan Alig; Sheren Younes; Lianna J Marks; Chelsea Pinnix; Francisco Vega; Raphael Steiner; Priya Kumar; Heidi Mocikova; Alice Sykorova; Vit Prochazka; Cristiane Milito; Pamela Allen; Darina Paulino; Alan Ramsay; Timothy Flerlage; Monica Palese; Robert West; ChunFang Zhu; Troy Noordenbos; Joseph Schroers-Martin; Shuchun Zhao; Natalie J Park; Anusha Kalbasi; Everett J Moding; Aaron M Newman; Ranjana H Advani; Richard T Hoppe; Maximilian Diehn; Yasodha Natkunam; Ash A Alizadeh; Michael Sargent Binkley

doi:10.1038/s41467-025-63339-9

Distinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma

Nat Commun. 2025 Sep 26;16(1):8473. doi: 10.1038/s41467-025-63339-9.

Authors

Ajay Subramanian^#¹, Shengqin Su^#¹, Jamie Flerlage², Stefan Alig³, Sheren Younes⁴, Lianna J Marks⁵, Chelsea Pinnix⁶, Francisco Vega⁷, Raphael Steiner⁸, Priya Kumar⁹, Heidi Mocikova¹⁰, Alice Sykorova¹¹, Vit Prochazka¹², Cristiane Milito¹³, Pamela Allen¹⁴, Darina Paulino¹⁴, Alan Ramsay¹⁵, Timothy Flerlage¹⁶, Monica Palese², Robert West⁴, ChunFang Zhu⁴, Troy Noordenbos³, Joseph Schroers-Martin³, Shuchun Zhao⁴, Natalie J Park¹, Anusha Kalbasi¹, Everett J Moding¹, Aaron M Newman¹⁷, Ranjana H Advani³, Richard T Hoppe¹, Maximilian Diehn¹, Yasodha Natkunam⁴, Ash A Alizadeh³, Michael Sargent Binkley¹⁸

Affiliations

¹ Department of Radiation Oncology, Stanford University, Stanford, CA, USA.
² Department of Pediatrics, University of Rochester, Rochester, NY, USA.
³ Department of Medicine, Division of Oncology, Stanford University, Stanford, CA, USA.
⁴ Department of Pathology, Stanford University, Stanford, CA, USA.
⁵ Department of Pediatrics, Division of Pediatric Hematology/Oncology, Stanford University, Stanford, CA, USA.
⁶ Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹⁰ Department of Hematology, Fakultni nemocnice Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czechia.
¹¹ 4th Department of Internal Medicine - Hematology, University Hospital and Faculty of Medicine, Hradec Kralove, Czechia.
¹² Department of Hemato-oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Olomouc, Czechia.
¹³ Department of Pathology at the Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
¹⁴ Department of Hematology & Oncology Winship Cancer Institute of Emory University, Atlanta, GA, USA.
¹⁵ University College London Hospitals NHS Foundation Trust, London, UK.
¹⁶ Department of Infectious Diseases, University of Rochester, Rochester, NY, USA.
¹⁷ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
¹⁸ Department of Radiation Oncology, Stanford University, Stanford, CA, USA. msb996@stanford.edu.

^# Contributed equally.

Abstract

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.

MeSH terms

Adult
CD8-Positive T-Lymphocytes / immunology
Dendritic Cells / immunology
Dendritic Cells / metabolism
Female
Hodgkin Disease* / genetics
Hodgkin Disease* / immunology
Hodgkin Disease* / pathology
Humans
Lymphocytes* / immunology
Lymphocytes* / pathology
Male
Middle Aged
Transcriptome
Tumor Microenvironment* / genetics
Tumor Microenvironment* / immunology

Abstract

MeSH terms

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