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 and Michael Sargent Binkley ()
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63339-9

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