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Cancer Immunology Research
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Research Article

An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses

Ismail M. Meraz, Mourad Majidi, Feng Meng, RuPing Shao, Min Jin Ha, Shinya Neri, Bingliang Fang, Steven H. Lin, Peggy T. Tinkey, Elizabeth J. Shpall, Jeffrey Morris and Jack A. Roth
Ismail M. Meraz
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: imeraz@mdanderson.org
Mourad Majidi
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Feng Meng
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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RuPing Shao
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Min Jin Ha
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • ORCID record for Min Jin Ha
Shinya Neri
4Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Bingliang Fang
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Steven H. Lin
4Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Peggy T. Tinkey
5Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Elizabeth J. Shpall
6Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jeffrey Morris
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jack A. Roth
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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DOI: 10.1158/2326-6066.CIR-18-0874
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Abstract

Human tumor xenograft models do not replicate the human immune system and tumor microenvironment. We developed an improved humanized mouse model, derived from fresh cord blood CD34+ stem cells (CD34+ HSC), and combined it with lung cancer cell line–derived human xenografts or patient-derived xenografts (Hu-PDX). Fresh CD34+ HSCs could reconstitute detectable mature human leukocytes (hCD45+) in mice at four weeks without the onset of graft-versus-host disease (GVHD). Repopulated human T cells, B cells, natural killer (NK) cells, dendritic cells (DC), and myeloid-derived suppressor cells (MDSC) increased in peripheral blood, spleen, and bone marrow over time. Although cultured CD34+ HSCs labeled with luciferase could be detected in mice, the cultured HSCs did not develop into mature human immune cells by four weeks, unlike fresh CD34+ HSCs. Ex vivo, reconstituted T cells, obtained from the tumor-bearing humanized mice, secreted IFNγ upon treatment with phorbol myristate acetate (PMA) or exposure to human A549 lung tumor cells and mediated antigen-specific CTL responses, indicating functional activity. Growth of engrafted PDXs and tumor xenografts was not dependent on the human leukocyte antigen status of the donor. Treatment with the anti–PD-1 checkpoint inhibitors pembrolizumab or nivolumab inhibited tumor growth in humanized mice significantly, and correlated with an increased number of CTLs and decreased MDSCs, regardless of the donor HLA type. In conclusion, fresh CD34+HSCs are more effective than their expanded counterparts in humanizing mice, and do so in a shorter time. The Hu-PDX model provides an improved platform for evaluation of immunotherapy.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2019;XX:XX–XX

  • Received December 7, 2018.
  • Revision received March 8, 2019.
  • Accepted May 31, 2019.
  • Published first June 11, 2019.
  • ©2019 American Association for Cancer Research.
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This OnlineFirst version was published on June 26, 2019
doi: 10.1158/2326-6066.CIR-18-0874

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An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses
Ismail M. Meraz, Mourad Majidi, Feng Meng, RuPing Shao, Min Jin Ha, Shinya Neri, Bingliang Fang, Steven H. Lin, Peggy T. Tinkey, Elizabeth J. Shpall, Jeffrey Morris and Jack A. Roth
Cancer Immunol Res June 26 2019 DOI: 10.1158/2326-6066.CIR-18-0874

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An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses
Ismail M. Meraz, Mourad Majidi, Feng Meng, RuPing Shao, Min Jin Ha, Shinya Neri, Bingliang Fang, Steven H. Lin, Peggy T. Tinkey, Elizabeth J. Shpall, Jeffrey Morris and Jack A. Roth
Cancer Immunol Res June 26 2019 DOI: 10.1158/2326-6066.CIR-18-0874
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