Next-generation humanized patient-derived xenograft mouse model for pre-clinical antibody studies in neuroblastoma
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ORIGINAL ARTICLE
Next‑generation humanized patient‑derived xenograft mouse model for pre‑clinical antibody studies in neuroblastoma Rosa Nguyen1,2 · Anand G. Patel1,3 · Lyra M. Griffiths3 · Jason Dapper3 · Elizabeth A. Stewart1,3 · Jim Houston3 · Melissa Johnson4 · Walter J. Akers4 · Wayne L. Furman1 · Michael A. Dyer3 Received: 28 October 2019 / Accepted: 31 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Faithful tumor mouse models are fundamental research tools to advance the field of immuno-oncology (IO). This is particularly relevant in diseases with low incidence, as in the case of pediatric malignancies, that rely on pre-clinical therapeutic development. However, conventional syngeneic and genetically engineered mouse models fail to recapitulate the tumor heterogeneity and microenvironmental complexity of human pathology that are essential determinants of cancer-directed immunity. Here, we characterize a novel mouse model that supports human natural killer (NK) cell development and engraftment of neuroblastoma orthotopic patient-derived xenograft (O-PDX) for pre-clinical antibody and cytokine testing. Using cytotoxicity assays, single-cell RNA-sequencing, and multi-color flow cytometry, we demonstrate that NK cells that develop in the humanized mice are fully licensed to execute NK cell cytotoxicity, permit human tumor engraftment, but can be therapeutically redirected to induce antibody-dependent cell-mediated cytotoxicity (ADCC). Although these cells share phenotypic and molecular features with healthy controls, we noted that they lacked an NK cell subset, termed activated NK cells, that is characterized by differentially expressed genes that are induced by cytokine activation. Because this subset of genes is also downregulated in patients with neuroblastoma compared to healthy controls, we hypothesize that this finding could be due to tumor-mediated suppressive effects. Thus, despite its technical complexity, this humanized patient-derived xenograft mouse model could serve as a faithful system for future testing of IO applications and studies of underlying immunologic processes. Keywords Pediatric oncology · Natural killer cells · Neuroblastoma · Antibody therapy
Rosa Nguyen and Anand G. Patel have contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02713-6) contains supplementary material, which is available to authorized users. * Rosa Nguyen [email protected] 1
Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
2
Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
3
Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
4
Center for In Vivo Imaging and Therapeutics (CIVIT), St. Jude Children’s Research Hospital, Memphis, TN, USA
Abbreviations ACT Adoptive cell transfer ADCC Antibody-dependent cell-mediated cytotoxicity CAR Chimeric antigen receptor E.T Effector-to-ta
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