Analysis and validation of human targets and treatments using a hepatocellular carcinoma‐immune humanized mouse model

Analysis and validation of human targets and treatments using a hepatocellular carcinoma‐immune humanized mouse model
Title:
Analysis and validation of human targets and treatments using a hepatocellular carcinoma‐immune humanized mouse model
Other Titles:
Hepatology
Keywords:
Publication Date:
18 March 2021
Citation:
Zhao, Y., Wang, J., Liu, W. N., Fong, S. Y., Shuen, T. W. H., Liu, M., … Chen, Q. (2021). Analysis and validation of human targets and treatments using a hepatocellular carcinoma‐immune humanized mouse model. Hepatology. doi:10.1002/hep.31812
Abstract:
Background & Aims: Recent development of multiple treatments for human hepatocellular carcinoma (HCC) has allowed us to select combination therapy to enhance the effectiveness of monotherapy. Optimal selection of therapies bases on both HCC and its microenvironment. Therefore, it is critical to develop and validate new pre-clinical animal models for testing clinical therapeutic solutions. Approach & Results: We established cell line-based or patient-derived xenograft hepatocellular carcinoma-immune humanized subcutaneous and orthotopic mouse models. Mice were injected with human specific antibodies to deplete human immune cell. We analyzed the transcription profiles of HCC cells and human immune cells by Real-Time PCR and RNA-sequencing. The protein level of HCC tumor cells/tissues or human immune cells was determined by flow cytometry, western blot and immunohistochemistry. The HCC tumor size was measured after single, dual and triple-combination treatment using C188-9, bevacizumab, and pembrolizumab. In our study, human immune cells in the tumor microenvironment were strongly selected and modulated by HCC, which promoted the activation of the IL-6/JAK2/STAT3 signal pathway in tumor cells and led to augmented HCC proliferation and angiogenesis by releasing angiogenic cytokines in HCC-immune humanized mice. In particular, intratumor hCD14+ cells could produce IL-33 via DAMP-TLR4-AP1, which up-regulated IL-6 in other intratumor immune cells and activated the JAK2/STAT3 pathway in HCC. Specific knockdown of CD14 gene in human monocytes could impair IL-33 production induced by cell lysates. Subsequently, we evaluated the in vivo anti-HCC effect of C188-9, bevacizumab, and pembrolizumab. The results showed that the anti-HCC effect of triple-combination therapy was superior to that of single or dual treatments. Conclusions: HCC-immune humanized mouse models are suitable for identifying targets from cancer and immune components and testing combinational therapies.
License type:
Publisher Copyright
Funding Info:
This research / project is supported by the National Medical Research Council, Singapore - VICTORY Programme
Grant Reference no. : NMRC/OFLCG/003/2018

This research / project is supported by the National Medical Research Council, Singapore - Senior Clinician Scientist Award
Grant Reference no. : NMRC/CSASI16nov006

This research / project is supported by the National Medical Research Council, Singapore - Eradication of HBV TCR Program
Grant Reference no. : NMRC/TCR/014-NUHS/2015

This research / project is supported by the National Medical Research Council, Singapore - Clinician Scientist-Individual Research Grant
Grant Reference no. : CIRG19may-0051

This research / project is supported by the National Research Foundation, Singapore - National Research Foundation Singapore Fellowship
Grant Reference no. : NRF-NRFF2017-03

This research / project is supported by the National Research Foundation, Singapore - NRF-ISF joint grant
Grant Reference no. : NRF2019-NRF-ISF003-3127

This research / project is supported by the National Research Foundation, Singapore - NRF-CRP grant
Grant Reference no. : NRF2016-CRP001-103

This research / project is supported by the Agency for Science, Technology and Research - IAF-PP
Grant Reference no. : H18/01/a0/022
Description:
This is the peer reviewed version of the following article: Zhao, Y., Wang, J., Liu, W. N., Fong, S. Y., Shuen, T. W. H., Liu, M., … Chen, Q. (2021). Analysis and validation of human targets and treatments using a hepatocellular carcinoma‐immune humanized mouse model. Hepatology. doi:10.1002/hep.31812, which has been published in final form at http://dx.doi.org/10.1002/hep.31812. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
ISSN:
0270-9139
1527-3350
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