A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment

Jenna M Kastenschmidt; Joseph G Schroers-Martin; Brian J Sworder; Suhas Sureshchandra; Michael S Khodadoust; Chih Long Liu; Mari Olsen; David M Kurtz; Maximilian Diehn; Lisa E Wagar; Ash A Alizadeh

doi:10.1016/j.stem.2024.01.012

A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment

Cell Stem Cell. 2024 Mar 7;31(3):410-420.e4. doi: 10.1016/j.stem.2024.01.012. Epub 2024 Feb 22.

Affiliations

¹ Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA 92617, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92617, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92617, USA; Cancer Research Institute, University of California, Irvine, Irvine, CA 92617, USA.
² Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
³ Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
⁴ Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Physiology & Biophysics, University of California, Irvine, Irvine, CA 92617, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92617, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92617, USA; Cancer Research Institute, University of California, Irvine, Irvine, CA 92617, USA. Electronic address: lwagar@hs.uci.edu.
⁶ Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.

PMID: 38402619
PMCID: PMC10960522 (available on 2025-03-07)
DOI: 10.1016/j.stem.2024.01.012

Abstract

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.

Keywords: T follicular helper cells; bispecific antibody therapy; follicular lymphoma; patient-derived lymphoma organoids; precision medicine; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

B-Lymphocytes
Humans
Lymphoma, Follicular* / diagnosis
Lymphoma, Follicular* / genetics
Lymphoma, Follicular* / therapy
Organoids
Receptors, Antigen, T-Cell
Tumor Microenvironment

Substances

Receptors, Antigen, T-Cell

A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment

Authors

Affiliations

Abstract

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MeSH terms

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