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.

4th Department of Internal Medicine Hematology University Hospital and Faculty of Medicine Hradec Kralove Czechia

Department of Biomedical Data Science Stanford University Stanford CA USA

Department of Hemato oncology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Olomouc Czechia

Department of Hematology and Oncology Winship Cancer Institute of Emory University Atlanta GA USA

Department of Hematology Fakultni nemocnice Kralovske Vinohrady and 3rd Faculty of Medicine Charles University Prague Czechia

Department of Hematopathology MD Anderson Cancer Center Houston TX USA

Department of Infectious Diseases University of Rochester Rochester NY USA

Department of Lymphoma and Myeloma MD Anderson Cancer Center Houston TX USA

Department of Medicine Division of Oncology Stanford University Stanford CA USA

Department of Pathology at the Federal University of Rio de Janeiro Rio de Janeiro Brazil

Department of Pathology St Jude Children's Research Hospital Memphis TN USA

Department of Pathology Stanford University Stanford CA USA

Department of Pediatrics Division of Pediatric Hematology Oncology Stanford University Stanford CA USA

Department of Pediatrics University of Rochester Rochester NY USA

Department of Radiation Oncology MD Anderson Cancer Center Houston TX USA

Department of Radiation Oncology Stanford University Stanford CA USA

University College London Hospitals NHS Foundation Trust London UK

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