Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy

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, non-obese 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; nonsmall 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.-Wang, M., Yao, L.-C., Cheng, M., Cai, D., Martinek, J., Pan, C.-X., Shi, W., Ma, A.-H., De Vere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., Keck, J. G. Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2017 Nov 16 [Epub ahead of print]

Minan Wang, Li-Chin Yao, Mingshan Cheng, Danying Cai, Jan Martinek, Chong-Xian Pan, Wei Shi, Ai-Hong Ma, Ralph W De Vere White, Susan Airhart, Edison T Liu, Jacques Banchereau, Michael A Brehm, Dale L Greiner, Leonard D Shultz, Karolina Palucka, James G Keck

Department of In Vivo Pharmacology Services, The Jackson Laboratory, Sacramento, California, USA; ., Department of In Vivo Pharmacology Services, The Jackson Laboratory, Sacramento, California, USA., Department of Immunology, The Jackson Laboratory, Farmington, Connecticut, USA., Department of Urology, Davis Comprehensive Cancer Center, University of California, Davis, Davis, California, USA., Department of Biochemistry and Molecular Medicine, Davis Comprehensive Cancer Center, University of California, Davis, Davis, California, USA., Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA., Department of Immunology, The Jackson Laboratory, Bar Harbor, Maine, USA.