Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy.
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 promis...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0219517 |
| _version_ | 1797660698861371392 |
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| author | Carina Hage Sabine Hoves Mailin Ashoff Veronika Schandl Stefan Hört Natascha Rieder Christian Heichinger Marco Berrera Carola H Ries Fabian Kiessling Thomas Pöschinger |
| author_facet | Carina Hage Sabine Hoves Mailin Ashoff Veronika Schandl Stefan Hört Natascha Rieder Christian Heichinger Marco Berrera Carola H Ries Fabian Kiessling Thomas Pöschinger |
| author_sort | Carina Hage |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T18:34:44Z |
| format | Article |
| id | doaj.art-32aaa4fc8bf8483789acc338886f0921 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-03-11T18:34:44Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-32aaa4fc8bf8483789acc338886f09212023-10-13T05:31:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01147e021951710.1371/journal.pone.0219517Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy.Carina HageSabine HovesMailin AshoffVeronika SchandlStefan HörtNatascha RiederChristian HeichingerMarco BerreraCarola H RiesFabian KiesslingThomas PöschingerHepatocellular 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.https://doi.org/10.1371/journal.pone.0219517 |
| spellingShingle | Carina Hage Sabine Hoves Mailin Ashoff Veronika Schandl Stefan Hört Natascha Rieder Christian Heichinger Marco Berrera Carola H Ries Fabian Kiessling Thomas Pöschinger Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy. PLoS ONE |
| title | Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy. |
| title_full | Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy. |
| title_fullStr | Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy. |
| title_full_unstemmed | Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy. |
| title_short | Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy. |
| title_sort | characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy |
| url | https://doi.org/10.1371/journal.pone.0219517 |
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