A 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.
Competing Interests: Declaration of interests J.M.K., J.G.S.-M., B.J.S., M.D., L.E.W., and A.A.A. have submitted a provisional patent application (filed by Stanford University on 06/12/2023 with application number 63/507,692) on the development and applications of PDLOs. A.A.A. reports ownership interest in CiberMed, FortySeven Inc., and Foresight Diagnostics; patent filings related to cancer biomarkers; research funding from Bristol Myers Squibb and Celgene; and paid consultancy from Genentech, Karyopharm, Roche, Chugai, Gilead, and Celgene. L.E.W. reports research funding (unrelated to this study) from F. Hoffman La Roche.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)