Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines
Hypochlorous acid (HOCl)-treated whole tumor cell lysates (Ox-L) have been shown to be more immunogenic when used as an antigen source for therapeutic dendritic cell (DC)-based vaccines, improving downstream immune responses both in vitro and in vivo. However, the mechanisms behind the improved immu...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/8/2/271 |
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| author | Michele Graciotti Fabio Marino HuiSong Pak Petra Baumgaertner Anne-Christine Thierry Johanna Chiffelle Marta A. S. Perez Vincent Zoete Alexandre Harari Michal Bassani-Sternberg Lana E. Kandalaft |
| author_facet | Michele Graciotti Fabio Marino HuiSong Pak Petra Baumgaertner Anne-Christine Thierry Johanna Chiffelle Marta A. S. Perez Vincent Zoete Alexandre Harari Michal Bassani-Sternberg Lana E. Kandalaft |
| author_sort | Michele Graciotti |
| collection | DOAJ |
| description | Hypochlorous acid (HOCl)-treated whole tumor cell lysates (Ox-L) have been shown to be more immunogenic when used as an antigen source for therapeutic dendritic cell (DC)-based vaccines, improving downstream immune responses both in vitro and in vivo. However, the mechanisms behind the improved immunogenicity are still elusive. To address this question, we conducted a proteomic and immunopeptidomics analyses to map modifications and alterations introduced by HOCl treatment using a human melanoma cell line as a model system. First, we show that one-hour HOCl incubation readily induces extensive protein oxidation, mitochondrial biogenesis, and increased expression of chaperones and antioxidant proteins, all features indicative of an activation of oxidative stress-response pathways. Characterization of the DC proteome after loading with HOCl treated tumor lysate (Ox-L) showed no significant difference compared to loading with untreated whole tumor lysate (FT-L). On the other hand, detailed immunopeptidomic analyses on monocyte-derived DCs (mo-DCs) revealed a great increase in human leukocyte antigen class II (HLA-II) presentation in mo-DCs loaded with Ox-L compared to the FT-L control. Further, 2026 HLA-II ligands uniquely presented on Ox-L-loaded mo-DCs were identified. In comparison, identities and intensities of HLA class I (HLA-I) ligands were overall comparable. We found that HLA-II ligands uniquely presented by DCs loaded with Ox-L were more solvent exposed in the structures of their source proteins, contrary to what has been hypothesized so far. Analyses from a phase I clinical trial showed that vaccinating patients using autologous Ox-L as an antigen source efficiently induces polyfunctional vaccine-specific CD4+ T cell responses. Hence, these results suggest that the increased immunogenicity of Ox-L is, at least in part, due to qualitative and quantitative changes in the HLA-II ligandome, potentially leading to an increased HLA-II dependent stimulation of the T cell compartment (i.e., CD4+ T cell responses). These results further contribute to the development of more effective and immunogenic DC-based vaccines and to the molecular understanding of the mechanism behind HOCl adjuvant properties. |
| first_indexed | 2024-03-10T19:24:38Z |
| format | Article |
| id | doaj.art-4cb72e9288fc4a06a2a4661378814de5 |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-10T19:24:38Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-4cb72e9288fc4a06a2a4661378814de52023-11-20T02:38:24ZengMDPI AGVaccines2076-393X2020-06-018227110.3390/vaccines8020271Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based VaccinesMichele Graciotti0Fabio Marino1HuiSong Pak2Petra Baumgaertner3Anne-Christine Thierry4Johanna Chiffelle5Marta A. S. Perez6Vincent Zoete7Alexandre Harari8Michal Bassani-Sternberg9Lana E. Kandalaft10Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, SwitzerlandHypochlorous acid (HOCl)-treated whole tumor cell lysates (Ox-L) have been shown to be more immunogenic when used as an antigen source for therapeutic dendritic cell (DC)-based vaccines, improving downstream immune responses both in vitro and in vivo. However, the mechanisms behind the improved immunogenicity are still elusive. To address this question, we conducted a proteomic and immunopeptidomics analyses to map modifications and alterations introduced by HOCl treatment using a human melanoma cell line as a model system. First, we show that one-hour HOCl incubation readily induces extensive protein oxidation, mitochondrial biogenesis, and increased expression of chaperones and antioxidant proteins, all features indicative of an activation of oxidative stress-response pathways. Characterization of the DC proteome after loading with HOCl treated tumor lysate (Ox-L) showed no significant difference compared to loading with untreated whole tumor lysate (FT-L). On the other hand, detailed immunopeptidomic analyses on monocyte-derived DCs (mo-DCs) revealed a great increase in human leukocyte antigen class II (HLA-II) presentation in mo-DCs loaded with Ox-L compared to the FT-L control. Further, 2026 HLA-II ligands uniquely presented on Ox-L-loaded mo-DCs were identified. In comparison, identities and intensities of HLA class I (HLA-I) ligands were overall comparable. We found that HLA-II ligands uniquely presented by DCs loaded with Ox-L were more solvent exposed in the structures of their source proteins, contrary to what has been hypothesized so far. Analyses from a phase I clinical trial showed that vaccinating patients using autologous Ox-L as an antigen source efficiently induces polyfunctional vaccine-specific CD4+ T cell responses. Hence, these results suggest that the increased immunogenicity of Ox-L is, at least in part, due to qualitative and quantitative changes in the HLA-II ligandome, potentially leading to an increased HLA-II dependent stimulation of the T cell compartment (i.e., CD4+ T cell responses). These results further contribute to the development of more effective and immunogenic DC-based vaccines and to the molecular understanding of the mechanism behind HOCl adjuvant properties.https://www.mdpi.com/2076-393X/8/2/271dendritic cellscancer vaccinesimmunotherapyproteomicsimmunopeptidomics |
| spellingShingle | Michele Graciotti Fabio Marino HuiSong Pak Petra Baumgaertner Anne-Christine Thierry Johanna Chiffelle Marta A. S. Perez Vincent Zoete Alexandre Harari Michal Bassani-Sternberg Lana E. Kandalaft Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines Vaccines dendritic cells cancer vaccines immunotherapy proteomics immunopeptidomics |
| title | Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines |
| title_full | Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines |
| title_fullStr | Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines |
| title_full_unstemmed | Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines |
| title_short | Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines |
| title_sort | deciphering the mechanisms of improved immunogenicity of hypochlorous acid treated antigens in anti cancer dendritic cell based vaccines |
| topic | dendritic cells cancer vaccines immunotherapy proteomics immunopeptidomics |
| url | https://www.mdpi.com/2076-393X/8/2/271 |
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