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  • Review Article
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Humanized mouse models for immuno-oncology research

Nature Reviews Clinical Oncology volume 20, pages 192–206 (2023)Cite this article

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Abstract

Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.

Key points

  • Humanized mouse models of cancer are immunodeficient mice co-engrafted with human tumours and immune cells, and are used in immuno-oncology research with potential for clinical translation.

  • The limitations of humanized mouse models include restricted development of mature innate immune cells, a lack of HLA molecules, limited ability to generate antigen-specific antibody responses, and a dearth of lymph node structures and germinal centres.

  • Given the complexity of generating humanized mice for experimental studies, the advantages and limitations of each specific model need to be carefully considered and assessed to ensure the highest probability of an effective study.

  • Next-generation humanized mouse models are being generated to better recapitulate the development of human innate and adaptive immunity. The development and use of novel humanized mouse platforms will accelerate the discovery and testing of new immunotherapies for patients with cancer.

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Fig. 1: Dynamics of human immune system development in humanized mouse models.
Fig. 2: Building resources for human tumour avatar studies.

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Acknowledgements

The work of the authors is supported in part by grants from the US National Institutes of Health (CA034196 (to L.D.S.), AI132963 (to L.D.S. and M.A.B.), OD026440 (to D.L.G., L.D.S. and M.A.B.)) and funding from the Japan Society for the Promotion of Science (to F.I.).

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Authors and Affiliations

  1. Program in Molecular Medicine, The University of Massachusetts Chan Medical School, Worcester, MA, USA

    Jane Chuprin, Hannah Buettner, Mina O. Seedhom, Dale L. Greiner & Michael A. Brehm

  2. Department of Molecular, Cell and Cancer Biology, The University of Massachusetts Chan Medical School, Worcester, MA, USA

    Jane Chuprin

  3. Department of Surgery, The University of Massachusetts Chan Medical School, Worcester, MA, USA

    Hannah Buettner

  4. The Jackson Laboratory, Sacramento, CA, USA

    James G. Keck

  5. Riken Center for Integrative Medical Sciences, Yokohama, Japan

    Fumihiko Ishikawa

  6. The Jackson Laboratory, Bar Harbour, ME, USA

    Leonard D. Shultz

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Contributions

J.C., H.B., M.O.S., D.L.G., L.D.S. and M.A.B. researched data for the article; J.C., H.B., D.L.G., J.G.K., F.I., L.D.S. and M.A.B. contributed substantially to discussions of content; J.C., H.B., L.D.S. and M.A.B. wrote the article; and all authors reviewed and/or edited the manuscript before submission.

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Correspondence to Michael A. Brehm.

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Competing interests

D.L.G. and M.A.B. receive research support and are consultants for The Jackson Laboratory. J.G.K. and L.D.S. are employees at The Jackson Laboratory. NSG is a branded name marketed by The Jackson Laboratory, which commercializes several NSG and NSG-related strains discussed in this Review. The Jackson Laboratory also provides commercial oncology services.

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Nature Reviews Clinical Oncology thanks Q. Chen, T. Pitts and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Chuprin, J., Buettner, H., Seedhom, M.O. et al. Humanized mouse models for immuno-oncology research. Nat Rev Clin Oncol 20, 192–206 (2023). https://doi.org/10.1038/s41571-022-00721-2

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