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Updated: Sep 2, 2025
A "Patient-Like" Orthotopic Syngeneic Mouse Model of Hepatocellular Carcinoma Metastasis
Published on: October 24, 2015
Profiling of syngeneic mouse HCC tumor models as a framework to understand anti-PD-1 sensitive tumor
Daniel J Zabransky1, Ludmila Danilova1, James M Leatherman1
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center , the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine , Baltimore , Maryland , USA.
Background And Aims:
The treatment of hepatocellular carcinoma (HCC) has been transformed by the use of immune checkpoint inhibitors. However, most patients with HCC do not benefit from treatment with immunotherapy. There is an urgent need to understand the mechanisms that underlie response or resistance to immunotherapy for patients with HCC. The use of syngeneic mouse models that closely recapitulate the heterogeneity of human HCC will provide opportunities to examine the complex interactions between cancer cells and nonmalignant cells in the tumor microenvironment.
Approach And Results:
We leverage a multifaceted approach that includes imaging mass cytometry and suspension cytometry by time of flight to profile the tumor microenvironments of the Hep53.4, Hepa 1-6, RIL-175, and TIBx (derivative of TIB-75) syngeneic mouse HCC models. The immune tumor microenvironments vary across these four models, and various immunosuppressive pathways exist at baseline in orthotopic liver tumors derived from these models. For instance, TIBx, which is resistant to anti-programmed cell death protein 1 therapy, contains a high proportion of "M2-like" tumor-associated macrophages with the potential to diminish antitumor immunity. Investigation of The Cancer Genome Atlas reveals that the baseline immunologic profiles of Hep53.4, RIL-175, and TIBx are broadly representative of human HCCs; however, Hepa 1-6 does not recapitulate the immune tumor microenvironment of the vast majority of human HCCs.
Conclusions:
There is a wide diversity in the immune tumor microenvironments in preclinical models and in human HCC, highlighting the need to use multiple syngeneic HCC models to improve the understanding of how to treat HCC through immune modulation.
Insights
Understanding why most hepatocellular carcinoma (HCC) patients resist immunotherapy requires studying diverse mouse models. These models reveal varied immune microenvironments crucial for developing effective HCC immune treatments.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Hepatocellular carcinoma (HCC) treatment is revolutionized by immune checkpoint inhibitors, yet many patients show resistance to immunotherapy.
- Understanding the mechanisms of immunotherapy response and resistance in HCC is critical for improving patient outcomes.
- Syngeneic mouse models mimicking human HCC heterogeneity are essential for studying tumor microenvironment interactions.
Purpose of the Study:
- To investigate the immune microenvironments of four syngeneic mouse HCC models (Hep53.4, Hepa 1-6, RIL-175, TIBx).
- To compare the immune profiles of these models with human HCC data from The Cancer Genome Atlas.
- To identify factors contributing to immunotherapy resistance in HCC.
Main Methods:
- Utilized imaging mass cytometry and suspension cytometry by time of flight to profile tumor microenvironments.
- Analyzed the immune cell composition and immunosuppressive pathways within the four HCC models.
- Compared the immunologic profiles of the mouse models with human HCC data.
Main Results:
- Significant variations in immune tumor microenvironments were observed across the four HCC models.
- Immunosuppressive pathways, such as M2-like macrophages in TIBx model, were identified.
- The Hep53.4, RIL-175, and TIBx models broadly represent human HCC immune profiles, while Hepa 1-6 does not.
Conclusions:
- Preclinical models and human HCC exhibit diverse immune tumor microenvironments.
- Multiple syngeneic HCC models are necessary to fully understand immune modulation strategies for HCC treatment.
- Further research using these models can guide the development of more effective immunotherapies for HCC.
