Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a high mortality rate due to limited treatment options. Hence, the response of HCC to different cancer immunotherapies is being intensively investigated in clinical trials. Immune checkpoint blockers (ICB) show promising results, albeit for a minority of HCC patients. Mouse models are commonly used to evaluate new therapeutic agents or regimens. However, to make clinical translation more successful, better characterized preclinical models are required. We therefore extensively investigated two immune-competent orthotopic HCC mouse models, namely transplanted Hep-55.1c and transgenic iAST, with respect to morphological, immunological and genetic traits and evaluated both models' responsiveness to immunotherapies. Hep-55.1c tumors were characterized by rich fibrous stroma, high mutational load and pronounced immune cell infiltrates, all of which are features of immune-responsive tumors. These characteristics were less distinct in iAST tumors, though these were highly vascularized. Cell depletion revealed that CD8+ T cells from iAST mice do not affect tumor growth and are tumor tolerant. This corresponds to the failure of single and combined ICB targeting PD-1 and CTLA-4. In contrast, combining anti-PD-1 and anti-CTLA-4 showed significant antitumor efficacy in the Hep-55.1c mouse model. Collectively, our data comprehensively characterize two immune-competent HCC mouse models representing ICB responsive and refractory characteristics. Our characterization confirms these models to be suitable for preclinical investigation of novel cancer immunotherapy approaches that aim to either deepen preexisting immune responses or generate de novo immunity against the tumor.
MeSH terms
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Animals
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Antigens, Polyomavirus Transforming / genetics
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Antineoplastic Agents, Immunological / pharmacology*
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Antineoplastic Agents, Immunological / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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CD8-Positive T-Lymphocytes / immunology
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CTLA-4 Antigen / antagonists & inhibitors
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CTLA-4 Antigen / immunology
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / immunology
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Cell Line, Tumor / transplantation
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Disease Models, Animal*
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor / methods
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Female
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Humans
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / genetics
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Liver Neoplasms / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / immunology
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Treatment Outcome
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / immunology
Substances
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Antigens, Polyomavirus Transforming
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Antineoplastic Agents, Immunological
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
Grants and funding
This study was sponsored by Roche. The funder provided support in the form of salaries for authors [CH, SH, MA, VS, SH, NR, CH, MB, CHR, TP], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.