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Gut. 2018 Oct;67(10):1845-1854. doi: 10.1136/gutjnl-2017-315201. Epub 2018 Mar 30.

Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy.

Author information

1
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
2
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
3
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
4
Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
5
Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore.
6
Division of Hepatobiliary and Liver Transplantation Surgery, National University Health System, Singapore.
7
Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore.
8
Department of Obstetrics and Gynaecology, KK Women's and Children's Hospital, Singapore.
9
Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore.
10
Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
11
Department of Haematology-Oncology, National University Cancer Institute, Singapore.
12
Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore.
13
Division of Surgical Oncology, National Cancer Center Singapore, Singapore.
14
Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore.
15
Duke-NUS Graduate Medical School, Singapore.
16
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Abstract

OBJECTIVE:

As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.

DESIGN:

Patient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg-/- (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.

RESULTS:

Similar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.

CONCLUSIONS:

Our work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.

KEYWORDS:

hepatocellular carcinoma; immunology; immunotherapy

PMID:
29602780
PMCID:
PMC6145285
DOI:
10.1136/gutjnl-2017-315201
[Indexed for MEDLINE]
Free PMC Article

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