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Molecular Cancer Research
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Tumor Microenvironment and Immunobiology

Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft

J. Jason Morton, Nathaniel Alzofon, Stephen B. Keysar, Tugs-Saikhan Chimed, Julie Reisinger, Loni Perrenoud, Phuong N. Le, Cera Nieto, Karina Gomez, Bettina Miller, Randi Yeager, Dexiang Gao, Aik-Choon Tan, Hilary Somerset, Theresa Medina, Xiao-Jing Wang, Jing H. Wang, William Robinson, Dennis R. Roop, Rene Gonzalez and Antonio Jimeno
J. Jason Morton
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Nathaniel Alzofon
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Stephen B. Keysar
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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  • ORCID record for Stephen B. Keysar
Tugs-Saikhan Chimed
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Julie Reisinger
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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  • ORCID record for Julie Reisinger
Loni Perrenoud
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Phuong N. Le
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Cera Nieto
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Karina Gomez
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Bettina Miller
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Randi Yeager
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Dexiang Gao
2Department of Biostatistics and Informatics, University of Colorado School of Medicine, Aurora, Colorado.
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Aik-Choon Tan
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
2Department of Biostatistics and Informatics, University of Colorado School of Medicine, Aurora, Colorado.
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Hilary Somerset
3Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado.
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Theresa Medina
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Xiao-Jing Wang
3Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado.
4Charles C. Gates Center for Regenerative Medicine, University of Colorado School of Medicine, Aurora, Colorado.
5Veterans Affairs Medical Center, VA Eastern Colorado Health Care System, Aurora, Colorado.
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Jing H. Wang
6Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado.
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William Robinson
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Dennis R. Roop
4Charles C. Gates Center for Regenerative Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Rene Gonzalez
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Antonio Jimeno
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
4Charles C. Gates Center for Regenerative Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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  • For correspondence: Antonio.Jimeno@cuanschutz.edu
DOI: 10.1158/1541-7786.MCR-20-0686 Published February 2021
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Abstract

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood–derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM, and NOD/SCID/IL2rg−/− (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non–HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)–related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines.

Implications: Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.

Footnotes

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

  • Mol Cancer Res 2021;19:346–57

  • Received August 5, 2020.
  • Revision received September 8, 2020.
  • Accepted October 14, 2020.
  • Published first October 21, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (2)
February 2021
Volume 19, Issue 2
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Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft
J. Jason Morton, Nathaniel Alzofon, Stephen B. Keysar, Tugs-Saikhan Chimed, Julie Reisinger, Loni Perrenoud, Phuong N. Le, Cera Nieto, Karina Gomez, Bettina Miller, Randi Yeager, Dexiang Gao, Aik-Choon Tan, Hilary Somerset, Theresa Medina, Xiao-Jing Wang, Jing H. Wang, William Robinson, Dennis R. Roop, Rene Gonzalez and Antonio Jimeno
Mol Cancer Res February 1 2021 (19) (2) 346-357; DOI: 10.1158/1541-7786.MCR-20-0686

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Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft
J. Jason Morton, Nathaniel Alzofon, Stephen B. Keysar, Tugs-Saikhan Chimed, Julie Reisinger, Loni Perrenoud, Phuong N. Le, Cera Nieto, Karina Gomez, Bettina Miller, Randi Yeager, Dexiang Gao, Aik-Choon Tan, Hilary Somerset, Theresa Medina, Xiao-Jing Wang, Jing H. Wang, William Robinson, Dennis R. Roop, Rene Gonzalez and Antonio Jimeno
Mol Cancer Res February 1 2021 (19) (2) 346-357; DOI: 10.1158/1541-7786.MCR-20-0686
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