biostudies-literatureSubramanian AU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)NCI NIH HHS8473https://www.ebi.ac.uk/biostudies/studies/S-EPMC12475200biostudies-literatureUnknown16(1)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 transcripNature communicationsDistinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma.PMC12475200K08 CA266824K08CA266824Binkley MSSykorova ADiehn MKumar PSubramanian ANewman AMVega FRamsay ASu SAlig SPaulino DProchazka VZhao SModing EJHoppe RTMarks LJPark NJPalese MMilito CNoordenbos TPinnix CKalbasi AZhu CSteiner RMocikova HAlizadeh AAYounes SFlerlage JAdvani RHSchroers-Martin JFlerlage TAllen PWest RNatkunam YfalseDistinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma.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 transcrip2025-01-01T00:00:00Z2025 Sep2026-06-03T21:34:22.766Z2026-05-01T03:11:31.701ZS-EPMC124752004100620310.1038/s41467-025-63339-9