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

Feb 26, 2024

Experts: 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

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.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

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ABOUT THE EXPERTS

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

Jenna M Kastenschmidt

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.

Joseph G Schroers-Martin

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.

Brian J Sworder

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.

Suhas Sureshchandra

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.

Michael S Khodadoust

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.

Chih Long Liu

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.

Mari Olsen

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.

David M Kurtz

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.

Maximilian Diehn

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.

Lisa E Wagar

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.

Ash A Alizadeh

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.