Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination
Vaccination using optimized strategies may increase response rates to immune checkpoint inhibitors (ICI) in some tumors. To enhance vaccine potency and improve thus responses to ICI, we analyzed the gene expression profile of an immunosuppressive dendritic cell (DC) population induced during vaccina...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.991311/full |
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| author | David Repáraz David Repáraz David Repáraz Marta Ruiz Marta Ruiz Marta Ruiz Leyre Silva Leyre Silva Leyre Silva Belén Aparicio Belén Aparicio Belén Aparicio Josune Egea Josune Egea Josune Egea Elizabeth Guruceaga Elizabeth Guruceaga Daniel Ajona Daniel Ajona Daniel Ajona Daniel Ajona Yaiza Senent Yaiza Senent Yaiza Senent Enrique Conde Enrique Conde Flor Navarro Sergio Barace Diego Alignani Diego Alignani Sandra Hervás-Stubbs Sandra Hervás-Stubbs Sandra Hervás-Stubbs Juan José Lasarte Juan José Lasarte Diana Llopiz Diana Llopiz Diana Llopiz Pablo Sarobe Pablo Sarobe Pablo Sarobe |
| author_facet | David Repáraz David Repáraz David Repáraz Marta Ruiz Marta Ruiz Marta Ruiz Leyre Silva Leyre Silva Leyre Silva Belén Aparicio Belén Aparicio Belén Aparicio Josune Egea Josune Egea Josune Egea Elizabeth Guruceaga Elizabeth Guruceaga Daniel Ajona Daniel Ajona Daniel Ajona Daniel Ajona Yaiza Senent Yaiza Senent Yaiza Senent Enrique Conde Enrique Conde Flor Navarro Sergio Barace Diego Alignani Diego Alignani Sandra Hervás-Stubbs Sandra Hervás-Stubbs Sandra Hervás-Stubbs Juan José Lasarte Juan José Lasarte Diana Llopiz Diana Llopiz Diana Llopiz Pablo Sarobe Pablo Sarobe Pablo Sarobe |
| author_sort | David Repáraz |
| collection | DOAJ |
| description | Vaccination using optimized strategies may increase response rates to immune checkpoint inhibitors (ICI) in some tumors. To enhance vaccine potency and improve thus responses to ICI, we analyzed the gene expression profile of an immunosuppressive dendritic cell (DC) population induced during vaccination, with the goal of identifying druggable inhibitory mechanisms. RNAseq studies revealed targetable genes, but their inhibition did not result in improved vaccines. However, we proved that immunosuppressive DC had a monocytic origin. Thus, monocyte depletion by gemcitabine administration reduced the generation of these DC and increased vaccine-induced immunity, which rejected about 20% of LLC-OVA and B16-OVA tumors, which are non-responders to anti-PD-1. This improved efficacy was associated with higher tumor T-cell infiltration and overexpression of PD-1/PD-L1. Therefore, the combination of vaccine + gemcitabine with anti-PD-1 was superior to anti-PD-1 monotherapy in both models. B16-OVA tumors benefited from a synergistic effect, reaching 75% of tumor rejection, but higher levels of exhausted T-cells in LLC-OVA tumors co-expressing PD-1, LAG3 and TIM3 precluded similar levels of efficacy. Our results indicate that gemcitabine is a suitable combination therapy with vaccines aimed at enhancing PD-1 therapies by targeting vaccine-induced immunosuppressive DC. |
| first_indexed | 2024-04-11T10:22:40Z |
| format | Article |
| id | doaj.art-53cc78736e214f2f9fa14856330d5191 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T10:22:40Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-53cc78736e214f2f9fa14856330d51912022-12-22T04:29:41ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.991311991311Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccinationDavid Repáraz0David Repáraz1David Repáraz2Marta Ruiz3Marta Ruiz4Marta Ruiz5Leyre Silva6Leyre Silva7Leyre Silva8Belén Aparicio9Belén Aparicio10Belén Aparicio11Josune Egea12Josune Egea13Josune Egea14Elizabeth Guruceaga15Elizabeth Guruceaga16Daniel Ajona17Daniel Ajona18Daniel Ajona19Daniel Ajona20Yaiza Senent21Yaiza Senent22Yaiza Senent23Enrique Conde24Enrique Conde25Flor Navarro26Sergio Barace27Diego Alignani28Diego Alignani29Sandra Hervás-Stubbs30Sandra Hervás-Stubbs31Sandra Hervás-Stubbs32Juan José Lasarte33Juan José Lasarte34Diana Llopiz35Diana Llopiz36Diana Llopiz37Pablo Sarobe38Pablo Sarobe39Pablo Sarobe40Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainDepartment of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainDepartment of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, SpainCentro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, SpainIdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, SpainVaccination using optimized strategies may increase response rates to immune checkpoint inhibitors (ICI) in some tumors. To enhance vaccine potency and improve thus responses to ICI, we analyzed the gene expression profile of an immunosuppressive dendritic cell (DC) population induced during vaccination, with the goal of identifying druggable inhibitory mechanisms. RNAseq studies revealed targetable genes, but their inhibition did not result in improved vaccines. However, we proved that immunosuppressive DC had a monocytic origin. Thus, monocyte depletion by gemcitabine administration reduced the generation of these DC and increased vaccine-induced immunity, which rejected about 20% of LLC-OVA and B16-OVA tumors, which are non-responders to anti-PD-1. This improved efficacy was associated with higher tumor T-cell infiltration and overexpression of PD-1/PD-L1. Therefore, the combination of vaccine + gemcitabine with anti-PD-1 was superior to anti-PD-1 monotherapy in both models. B16-OVA tumors benefited from a synergistic effect, reaching 75% of tumor rejection, but higher levels of exhausted T-cells in LLC-OVA tumors co-expressing PD-1, LAG3 and TIM3 precluded similar levels of efficacy. Our results indicate that gemcitabine is a suitable combination therapy with vaccines aimed at enhancing PD-1 therapies by targeting vaccine-induced immunosuppressive DC.https://www.frontiersin.org/articles/10.3389/fimmu.2022.991311/fullimmunosuppressive DCantitumor therapeutic vaccinationmonocyte depletionanti-PD-1gemcitabine |
| spellingShingle | David Repáraz David Repáraz David Repáraz Marta Ruiz Marta Ruiz Marta Ruiz Leyre Silva Leyre Silva Leyre Silva Belén Aparicio Belén Aparicio Belén Aparicio Josune Egea Josune Egea Josune Egea Elizabeth Guruceaga Elizabeth Guruceaga Daniel Ajona Daniel Ajona Daniel Ajona Daniel Ajona Yaiza Senent Yaiza Senent Yaiza Senent Enrique Conde Enrique Conde Flor Navarro Sergio Barace Diego Alignani Diego Alignani Sandra Hervás-Stubbs Sandra Hervás-Stubbs Sandra Hervás-Stubbs Juan José Lasarte Juan José Lasarte Diana Llopiz Diana Llopiz Diana Llopiz Pablo Sarobe Pablo Sarobe Pablo Sarobe Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination Frontiers in Immunology immunosuppressive DC antitumor therapeutic vaccination monocyte depletion anti-PD-1 gemcitabine |
| title | Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination |
| title_full | Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination |
| title_fullStr | Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination |
| title_full_unstemmed | Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination |
| title_short | Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination |
| title_sort | gemcitabine mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination |
| topic | immunosuppressive DC antitumor therapeutic vaccination monocyte depletion anti-PD-1 gemcitabine |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.991311/full |
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