Program in Molecular Medicine; Diabetes Center of Excellence
Cancer Biology | Immunoprophylaxis and Therapy | Neoplasms
Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- Prkdc(scid)IL2rg(tm1Wjl)/Sz (null; NSG) mice were transplanted with human (h)CD34(+) hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non-small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8(+) T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research.
checkpoint inhibitor, mouse model, patient-derived xenograft, pembrolizumab
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© The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) (http://creativecommons.org/licenses/by-nc/4.0/) which permits noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
FASEB J. 2018 Mar;32(3):1537-1549. doi: 10.1096/fj.201700740R. Epub 2018 Jan 3. Link to article on publisher's site
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Wang, Minan; Brehm, Michael A.; and Greiner, Dale L., "Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy" (2018). Open Access Articles. 3351.
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This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License