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Distinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma

Author

Listed:
  • Ajay Subramanian

    (Stanford University)

  • Shengqin Su

    (Stanford University)

  • Jamie Flerlage

    (University of Rochester)

  • Stefan Alig

    (Stanford University)

  • Sheren Younes

    (Stanford University)

  • Lianna J. Marks

    (Stanford University)

  • Chelsea Pinnix

    (MD Anderson Cancer Center)

  • Francisco Vega

    (MD Anderson Cancer Center)

  • Raphael Steiner

    (MD Anderson Cancer Center)

  • Priya Kumar

    (St. Jude Children’s Research Hospital)

  • Heidi Mocikova

    (Charles University)

  • Alice Sykorova

    (University Hospital and Faculty of Medicine)

  • Vit Prochazka

    (Palacky University and University Hospital Olomouc)

  • Cristiane Milito

    (Department of Pathology at the Federal University of Rio de Janeiro)

  • Pamela Allen

    (Department of Hematology & Oncology Winship Cancer Institute of Emory University)

  • Darina Paulino

    (Department of Hematology & Oncology Winship Cancer Institute of Emory University)

  • Alan Ramsay

    (University College London Hospitals NHS Foundation Trust)

  • Timothy Flerlage

    (University of Rochester)

  • Monica Palese

    (University of Rochester)

  • Robert West

    (Stanford University)

  • ChunFang Zhu

    (Stanford University)

  • Troy Noordenbos

    (Stanford University)

  • Joseph Schroers-Martin

    (Stanford University)

  • Shuchun Zhao

    (Stanford University)

  • Natalie J. Park

    (Stanford University)

  • Anusha Kalbasi

    (Stanford University)

  • Everett J. Moding

    (Stanford University)

  • Aaron M. Newman

    (Stanford University)

  • Ranjana H. Advani

    (Stanford University)

  • Richard T. Hoppe

    (Stanford University)

  • Maximilian Diehn

    (Stanford University)

  • Yasodha Natkunam

    (Stanford University)

  • Ash A. Alizadeh

    (Stanford University)

  • Michael Sargent Binkley

    (Stanford University)

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.

Suggested Citation

  • 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 & Vi, 2025. "Distinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63339-9
    DOI: 10.1038/s41467-025-63339-9
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    References listed on IDEAS

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    1. Yuechen Luo & Changlu Xu & Bing Wang & Qing Niu & Xiuhua Su & Yingnan Bai & Shuxian Zhu & Chunxiao Zhao & Yunyan Sun & Jiali Wang & Maolan Liu & Xiaolei Sun & Ge Song & Haidong Cui & Xiaoli Chen & Hui, 2021. "Single-cell transcriptomic analysis reveals disparate effector differentiation pathways in human Treg compartment," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Daphne Tsoucas & Rui Dong & Haide Chen & Qian Zhu & Guoji Guo & Guo-Cheng Yuan, 2019. "Accurate estimation of cell-type composition from gene expression data," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    3. Julia Merkenschlager & Shlomo Finkin & Victor Ramos & Julian Kraft & Melissa Cipolla & Carla R. Nowosad & Harald Hartweger & Wenzhu Zhang & Paul Dominic B. Olinares & Anna Gazumyan & Thiago Y. Oliveir, 2021. "Dynamic regulation of TFH selection during the germinal centre reaction," Nature, Nature, vol. 591(7850), pages 458-463, March.
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