Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma
Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/11/3397 |
| _version_ | 1797547698355699712 |
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| author | Leyre Silva Josune Egea Lorea Villanueva Marta Ruiz Diana Llopiz David Repáraz Belén Aparicio Aritz Lasarte-Cia Juan José Lasarte Marina Ruiz de Galarreta Amaia Lujambio Bruno Sangro Pablo Sarobe |
| author_facet | Leyre Silva Josune Egea Lorea Villanueva Marta Ruiz Diana Llopiz David Repáraz Belén Aparicio Aritz Lasarte-Cia Juan José Lasarte Marina Ruiz de Galarreta Amaia Lujambio Bruno Sangro Pablo Sarobe |
| author_sort | Leyre Silva |
| collection | DOAJ |
| description | Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered. |
| first_indexed | 2024-03-10T14:48:52Z |
| format | Article |
| id | doaj.art-76d8c721affa49cd8f1fbe9a8b8dedbb |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T14:48:52Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-76d8c721affa49cd8f1fbe9a8b8dedbb2023-11-20T21:11:03ZengMDPI AGCancers2072-66942020-11-011211339710.3390/cancers12113397Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular CarcinomaLeyre Silva0Josune Egea1Lorea Villanueva2Marta Ruiz3Diana Llopiz4David Repáraz5Belén Aparicio6Aritz Lasarte-Cia7Juan José Lasarte8Marina Ruiz de Galarreta9Amaia Lujambio10Bruno Sangro11Pablo Sarobe12Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainDepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USAIdiSNA, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, SpainTherapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered.https://www.mdpi.com/2072-6694/12/11/3397cold-inducible RNA binding proteintherapeutic vaccinationhepatocellular carcinomaimmune checkpoint inhibitors |
| spellingShingle | Leyre Silva Josune Egea Lorea Villanueva Marta Ruiz Diana Llopiz David Repáraz Belén Aparicio Aritz Lasarte-Cia Juan José Lasarte Marina Ruiz de Galarreta Amaia Lujambio Bruno Sangro Pablo Sarobe Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma Cancers cold-inducible RNA binding protein therapeutic vaccination hepatocellular carcinoma immune checkpoint inhibitors |
| title | Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma |
| title_full | Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma |
| title_fullStr | Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma |
| title_full_unstemmed | Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma |
| title_short | Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma |
| title_sort | cold inducible rna binding protein as a vaccination platform to enhance immunotherapeutic responses against hepatocellular carcinoma |
| topic | cold-inducible RNA binding protein therapeutic vaccination hepatocellular carcinoma immune checkpoint inhibitors |
| url | https://www.mdpi.com/2072-6694/12/11/3397 |
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