Journal Article

Distinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma

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

2025

Overview

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. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer. Here, the authors develop a NLPHL specific model to identify 34 distinct cell states across 14 cell types that co-occur within 3 lymphocyte predominant ecotypes (LPEs) for 171 cases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/39 / 38/91 / 45 / 631/67/1990/291/1556 / 631/67/327 / 82/80 / Adult / Biopsy / Cancer / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - metabolism / Ecosystems / Ecotypes / Female / Gene expression / Histocompatibility antigen HLA / Hodgkin Disease - genetics / Hodgkin Disease - immunology / Hodgkin Disease - pathology / Hodgkin's lymphoma / Humanities and Social Sciences / Humans / Immune checkpoint / Localization / Lymphocytes / Lymphocytes - immunology / Lymphocytes - pathology / Lymphocytes T / Lymphoma / Male / Microenvironments / Middle Aged / multidisciplinary / Patients / Science / Science (multidisciplinary) / Transcriptome / Transcriptomics / Tumor Microenvironment - genetics / Tumor Microenvironment - immunology