Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection
IntroductionTranscutaneous immunization (TCI) is a non-invasive vaccination method promoting strong cellular immune responses, crucial for the immunological rejection of cancer. Previously, we reported on the combined application of the TLR7 agonist imiquimod (IMQ) together with the anti-psoriatic d...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-09-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1238861/full |
| _version_ | 1827854667966578688 |
|---|---|
| author | Ann-Kathrin Hartmann Joschka Bartneck Jonas Pielenhofer Sophie Luise Meiser Danielle Arnold-Schild Matthias Klein Matthias Klein Michael Stassen Michael Stassen Hansjörg Schild Hansjörg Schild Hansjörg Schild Sabine Muth Sabine Muth Hans Christian Probst Hans Christian Probst Peter Langguth Peter Langguth Stephan Grabbe Stephan Grabbe Markus P. Radsak Markus P. Radsak Markus P. Radsak |
| author_facet | Ann-Kathrin Hartmann Joschka Bartneck Jonas Pielenhofer Sophie Luise Meiser Danielle Arnold-Schild Matthias Klein Matthias Klein Michael Stassen Michael Stassen Hansjörg Schild Hansjörg Schild Hansjörg Schild Sabine Muth Sabine Muth Hans Christian Probst Hans Christian Probst Peter Langguth Peter Langguth Stephan Grabbe Stephan Grabbe Markus P. Radsak Markus P. Radsak Markus P. Radsak |
| author_sort | Ann-Kathrin Hartmann |
| collection | DOAJ |
| description | IntroductionTranscutaneous immunization (TCI) is a non-invasive vaccination method promoting strong cellular immune responses, crucial for the immunological rejection of cancer. Previously, we reported on the combined application of the TLR7 agonist imiquimod (IMQ) together with the anti-psoriatic drug dithranol as novel TCI platform DIVA (dithranol/IMQ based vaccination). In extension of this work, we further optimized DIVA in terms of drug dose, application pattern and established a new IMQ formulation.MethodsC57BL/6 mice were treated on the ear skin with dithranol and IMQ-containing ointments together with ovalbumin-derived peptides. T cell responses were determined by flow cytometry and IFN-ɤ ELISpot assay, local skin inflammation was characterized by ear swelling.ResultsApplying the adjuvants on separate skin sites, a reduced number of specific CD8+ T cells with effector function was detectable, indicating that the local concurrence of adjuvants and peptide antigens is required for optimal vaccination. Likewise, changing the order of dithranol and IMQ resulted in an increased skin inflammatory reaction, but lower frequencies of antigen-specific CD8+ T cells indicating that dithranol is essential for superior T cell priming upon DIVA. Dispersing nanocrystalline IMQ in a spreadable formulation (IMI-Sol+) facilitated storage and application rendering comparable immune responses. DIVA applied one or two weeks after the first immunization resulted in a massive increase in antigen-specific T cells and up to a ten-fold increased memory response. Finally, in a prophylactic tumor setting, double but no single DIVA treatment enabled complete control of tumor growth, resulting in full tumor protection.DiscussionTaken together, the described optimized transcutaneous vaccination method leads to the generation of a strong cellular immune response enabling the effective control of tumor growth and has the potential for clinical development as a novel non-invasive vaccination method for peptide-based cancer vaccines in humans. |
| first_indexed | 2024-03-12T11:26:01Z |
| format | Article |
| id | doaj.art-45104fbc88c34ace9bbdff9da15c6608 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T11:26:01Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-45104fbc88c34ace9bbdff9da15c66082023-09-01T08:54:37ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.12388611238861Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejectionAnn-Kathrin Hartmann0Joschka Bartneck1Jonas Pielenhofer2Sophie Luise Meiser3Danielle Arnold-Schild4Matthias Klein5Matthias Klein6Michael Stassen7Michael Stassen8Hansjörg Schild9Hansjörg Schild10Hansjörg Schild11Sabine Muth12Sabine Muth13Hans Christian Probst14Hans Christian Probst15Peter Langguth16Peter Langguth17Stephan Grabbe18Stephan Grabbe19Markus P. Radsak20Markus P. Radsak21Markus P. Radsak22IIIrd Department of Medicine – Hematology and Oncology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyIIIrd Department of Medicine – Hematology and Oncology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyBiopharmaceutics and Pharmaceutical Technology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, GermanyBiopharmaceutics and Pharmaceutical Technology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, GermanyInstitute of Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyInstitute of Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyInstitute of Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyInstitute of Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyMainz Research School of Translational Biomedicine (TransMed), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyInstitute of Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyInstitute of Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyBiopharmaceutics and Pharmaceutical Technology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyMainz Research School of Translational Biomedicine (TransMed), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyIIIrd Department of Medicine – Hematology and Oncology, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyResearch Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyMainz Research School of Translational Biomedicine (TransMed), University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyIntroductionTranscutaneous immunization (TCI) is a non-invasive vaccination method promoting strong cellular immune responses, crucial for the immunological rejection of cancer. Previously, we reported on the combined application of the TLR7 agonist imiquimod (IMQ) together with the anti-psoriatic drug dithranol as novel TCI platform DIVA (dithranol/IMQ based vaccination). In extension of this work, we further optimized DIVA in terms of drug dose, application pattern and established a new IMQ formulation.MethodsC57BL/6 mice were treated on the ear skin with dithranol and IMQ-containing ointments together with ovalbumin-derived peptides. T cell responses were determined by flow cytometry and IFN-ɤ ELISpot assay, local skin inflammation was characterized by ear swelling.ResultsApplying the adjuvants on separate skin sites, a reduced number of specific CD8+ T cells with effector function was detectable, indicating that the local concurrence of adjuvants and peptide antigens is required for optimal vaccination. Likewise, changing the order of dithranol and IMQ resulted in an increased skin inflammatory reaction, but lower frequencies of antigen-specific CD8+ T cells indicating that dithranol is essential for superior T cell priming upon DIVA. Dispersing nanocrystalline IMQ in a spreadable formulation (IMI-Sol+) facilitated storage and application rendering comparable immune responses. DIVA applied one or two weeks after the first immunization resulted in a massive increase in antigen-specific T cells and up to a ten-fold increased memory response. Finally, in a prophylactic tumor setting, double but no single DIVA treatment enabled complete control of tumor growth, resulting in full tumor protection.DiscussionTaken together, the described optimized transcutaneous vaccination method leads to the generation of a strong cellular immune response enabling the effective control of tumor growth and has the potential for clinical development as a novel non-invasive vaccination method for peptide-based cancer vaccines in humans.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1238861/fulltrancutaneous immunizationimiquimod (IMQ)dithranol (anthralin)cytotoxic T lymphocytes (CTL)tumor rejection |
| spellingShingle | Ann-Kathrin Hartmann Joschka Bartneck Jonas Pielenhofer Sophie Luise Meiser Danielle Arnold-Schild Matthias Klein Matthias Klein Michael Stassen Michael Stassen Hansjörg Schild Hansjörg Schild Hansjörg Schild Sabine Muth Sabine Muth Hans Christian Probst Hans Christian Probst Peter Langguth Peter Langguth Stephan Grabbe Stephan Grabbe Markus P. Radsak Markus P. Radsak Markus P. Radsak Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection Frontiers in Immunology trancutaneous immunization imiquimod (IMQ) dithranol (anthralin) cytotoxic T lymphocytes (CTL) tumor rejection |
| title | Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection |
| title_full | Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection |
| title_fullStr | Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection |
| title_full_unstemmed | Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection |
| title_short | Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection |
| title_sort | optimized dithranol imiquimod based transcutaneous immunization enables tumor rejection |
| topic | trancutaneous immunization imiquimod (IMQ) dithranol (anthralin) cytotoxic T lymphocytes (CTL) tumor rejection |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1238861/full |
| work_keys_str_mv | AT annkathrinhartmann optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT joschkabartneck optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT jonaspielenhofer optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT sophieluisemeiser optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT daniellearnoldschild optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT matthiasklein optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT matthiasklein optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT michaelstassen optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT michaelstassen optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT hansjorgschild optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT hansjorgschild optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT hansjorgschild optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT sabinemuth optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT sabinemuth optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT hanschristianprobst optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT hanschristianprobst optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT peterlangguth optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT peterlangguth optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT stephangrabbe optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT stephangrabbe optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT markuspradsak optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT markuspradsak optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection AT markuspradsak optimizeddithranolimiquimodbasedtranscutaneousimmunizationenablestumorrejection |