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

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

doi:10.1096/fj.201700740R

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

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

Research output: Contribution to journal › Article

59 Scopus citations

Abstract

Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into themechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-Prkdc^scidIL2rg^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 patientderived xenografts [PDX;non-small cell lungcancer (NSCLC), sarcoma, bladder cancer, andtriple-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 NSGmice. Treatmentwith pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition inbothCDXandPDXtumorsinHuNSGbut not inNSGmice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearingHuNSG mice may represent an important, newmodel for preclinical immunotherapy research.

Original language	English (US)
Pages (from-to)	1537-1549
Number of pages	13
Journal	FASEB Journal
Volume	32
Issue number	3
DOIs	https://doi.org/10.1096/fj.201700740R
State	Published - Mar 1 2018

Keywords

Checkpoint inhibitor
Mouse model
Patient-derived xenograft
Pembrolizumab

ASJC Scopus subject areas

Biotechnology
Biochemistry
Molecular Biology
Genetics

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Wang, M., Yao, L. C., Cheng, M., Cai, D., Martinek, J., Pan, C-X., Shi, W., Ma, A. H., deVere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., & Keck, J. G. (2018). Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. FASEB Journal, 32(3), 1537-1549. https://doi.org/10.1096/fj.201700740R

Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. / Wang, Minan; Yao, Li Chin; Cheng, Mingshan; Cai, Danying; Martinek, Jan; Pan, Chong-Xian; Shi, Wei; Ma, Ai Hong; deVere White, Ralph W; Airhart, Susan; Liu, Edison T.; Banchereau, Jacques; Brehm, Michael A.; Greiner, Dale L.; Shultz, Leonard D.; Palucka, Karolina; Keck, James G.

In: FASEB Journal, Vol. 32, No. 3, 01.03.2018, p. 1537-1549.

Research output: Contribution to journal › Article

Wang, Minan ; Yao, Li Chin ; Cheng, Mingshan ; Cai, Danying ; Martinek, Jan ; Pan, Chong-Xian ; Shi, Wei ; Ma, Ai Hong ; deVere White, Ralph W ; Airhart, Susan ; Liu, Edison T. ; Banchereau, Jacques ; Brehm, Michael A. ; Greiner, Dale L. ; Shultz, Leonard D. ; Palucka, Karolina ; Keck, James G. / Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. In: FASEB Journal. 2018 ; Vol. 32, No. 3. pp. 1537-1549.

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abstract = "Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into themechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-PrkdcscidIL2rgtm1Wjl/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 patientderived xenografts [PDX;non-small cell lungcancer (NSCLC), sarcoma, bladder cancer, andtriple-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 NSGmice. Treatmentwith pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition inbothCDXandPDXtumorsinHuNSGbut not inNSGmice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearingHuNSG mice may represent an important, newmodel for preclinical immunotherapy research.",

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