biostudies-literatureKastenschmidt JMNCRR NIH HHSChao Family Comprehensive Cancer CenterNational Cancer InstituteNCI NIH HHSNIAMS NIH HHSNIHNIH HHS410-420.e4https://www.ebi.ac.uk/biostudies/studies/S-EPMC10960522biostudies-literatureUnknown31(3)Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.Cell stem cellA human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment.PMC10960522R01 CA233975P30 AR075047S10 OD021718U54 CA217378U01 CA194389P30 CA062203S10 OD010794S10 RR025496Alizadeh AASureshchandra SKhodadoust MSOlsen MDiehn MWagar LEKastenschmidt JMLiu CLSchroers-Martin JGSworder BJKurtz DMfalseA human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment.Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.2024-01-01T00:00:00Z2024 Mar2026-06-03T04:41:09.573Z2025-04-04T00:21:49.17ZS-EPMC109605223840261910.1016/j.stem.2024.01.012