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 journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1537-1549
Number of pages13
JournalFASEB Journal
Volume32
Issue number3
DOIs
StatePublished - Mar 1 2018

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Immunotherapy
Tumors
Immune system
Neoplasms
Heterografts
Programmed Cell Death 1 Receptor
Hematopoietic Stem Cells
Immune System
Growth
T-cells
Hematopoietic System
HLA Antigens
Stem cells
Human Development
Animals
Urinary Bladder Neoplasms
Sarcoma
Cells
Animal Models
Antibodies

Keywords

  • Checkpoint inhibitor
  • Mouse model
  • Patient-derived xenograft
  • Pembrolizumab

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Wang, M., Yao, L. C., Cheng, M., Cai, D., Martinek, J., Pan, C-X., ... 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 journalArticle

Wang, M, Yao, LC, Cheng, M, Cai, D, Martinek, J, Pan, C-X, Shi, W, Ma, AH, deVere White, RW, Airhart, S, Liu, ET, Banchereau, J, Brehm, MA, Greiner, DL, Shultz, LD, Palucka, K & Keck, JG 2018, 'Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy', FASEB Journal, vol. 32, no. 3, pp. 1537-1549. https://doi.org/10.1096/fj.201700740R
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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