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
2025-09-26
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.