Human cancer evolution in the context of a human immune system in mice

Odd L. Gammelgaard, Mikkel G. Terp, Birgitte Preiss, Henrik J. Ditzel*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Immunotherapy is one of the most promising cancer treatment modalities, but the lack of appropriate preclinical in vivo models hampers the development of novel immunotherapeutic strategies. Here, we studied the ability of transplanted human cancer cells to form primary tumors and metastasize in humanized immune system (HIS) mice created by transfer of CD34+ human hematopoietic stem cells. All tested transplanted cancer cell lines developed primary tumors that progressed nearly synchronously. Spontaneous lung and liver metastases developed from both orthotopic and ectopic transplanted cancer cells, and the ability to spread inversely correlated with the extent of CD8+ infiltration in the primary tumor. Further analysis revealed that interactions between the cancer model and the tumor-infiltrating lymphocytes created tumor microenvironments (TMEs) resembling clinical cancers. Some models were largely immune cell-excluding, while others appeared to develop adaptive resistance to immune-mediated destruction by increased expression of programmed death ligand 1 (PDL1) and recruitment of human regulatory T cells. Our data suggest that HIS mice may provide a promising in vivo tumor model for evaluating immune modulatory anticancer therapies. Moreover, our study identified different tumor models resembling specific types of human TMEs, rendering each beneficial for addressing disease-specific issues.

Original languageEnglish
JournalMolecular Oncology
Volume12
Issue number10
Pages (from-to)1797-1810
ISSN1574-7891
DOIs
Publication statusPublished - Oct 2018

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Immune System
Neoplasms
Tumor-Infiltrating Lymphocytes
Ligands
Cell Line
Lung
Liver

Keywords

  • adaptive resistance
  • cancer
  • humanized immune system mice
  • metastasis
  • programmed death ligand 1
  • tumor-infiltrating lymphocytes

Cite this

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title = "Human cancer evolution in the context of a human immune system in mice",
abstract = "Immunotherapy is one of the most promising cancer treatment modalities, but the lack of appropriate preclinical in vivo models hampers the development of novel immunotherapeutic strategies. Here, we studied the ability of transplanted human cancer cells to form primary tumors and metastasize in humanized immune system (HIS) mice created by transfer of CD34+ human hematopoietic stem cells. All tested transplanted cancer cell lines developed primary tumors that progressed nearly synchronously. Spontaneous lung and liver metastases developed from both orthotopic and ectopic transplanted cancer cells, and the ability to spread inversely correlated with the extent of CD8+ infiltration in the primary tumor. Further analysis revealed that interactions between the cancer model and the tumor-infiltrating lymphocytes created tumor microenvironments (TMEs) resembling clinical cancers. Some models were largely immune cell-excluding, while others appeared to develop adaptive resistance to immune-mediated destruction by increased expression of programmed death ligand 1 (PDL1) and recruitment of human regulatory T cells. Our data suggest that HIS mice may provide a promising in vivo tumor model for evaluating immune modulatory anticancer therapies. Moreover, our study identified different tumor models resembling specific types of human TMEs, rendering each beneficial for addressing disease-specific issues.",
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Human cancer evolution in the context of a human immune system in mice. / Gammelgaard, Odd L.; Terp, Mikkel G.; Preiss, Birgitte; Ditzel, Henrik J.

In: Molecular Oncology, Vol. 12, No. 10, 10.2018, p. 1797-1810.

Research output: Contribution to journalJournal articleResearchpeer-review

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