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

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.

journal_name

Gut

journal_title

Gut

authors

Zhao Y,Shuen TWH,Toh TB,Chan XY,Liu M,Tan SY,Fan Y,Yang H,Lyer SG,Bonney GK,Loh E,Chang KTE,Tan TC,Zhai W,Chan JKY,Chow EK,Chee CE,Lee GH,Dan YY,Chow PK,Toh HC,Lim SG,Chen Q

doi

10.1136/gutjnl-2017-315201

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

1845-1854

issue

eissn

0017-5749

issn

1468-3288

pii

gutjnl-2017-315201

journal_volume

pub_type

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