Humanized mouse models for immuno-oncology research

• Published in: Nature reviews. Clinical oncology Vol. 20; no. 3; pp. 192 - 206
• Main Authors: Chuprin, Jane, Buettner, Hannah, Seedhom, Mina O., Greiner, Dale L., Keck, James G., Ishikawa, Fumihiko, Shultz, Leonard D., Brehm, Michael A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2023; Nature Publishing Group
• Subjects: 631/154/1435; 631/67/70; Animal models; Animals; Biomarkers; Cancer immunotherapy; Disease Models, Animal; Drug development; Humans; Immune System; Immunodeficiency; Immunotherapy; Malignancy; Medicine; Medicine & Public Health; Mice; Neoplasms - therapy; Oncology; Review Article; Tumors
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-022-00721-2

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. Preclinical models that faithfully recapitulate interactions between the human immune system and tumours are necessary to evaluate human-specific immunotherapies in vivo; however, their number is currently limited. The authors of this Review discuss the currently available humanized mouse models, which are immunodeficient mice co-engrafted with human tumours and immune components, with a focus on their applicability in translational research. 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.