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Open AccessArticle

Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines

1
Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland
2
Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne (CHUV), 1011 Lausanne, Switzerland
3
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
*
Authors to whom correspondence should be addressed.
These authors equally contributed.
Vaccines 2020, 8(2), 271; https://doi.org/10.3390/vaccines8020271
Received: 14 May 2020 / Revised: 27 May 2020 / Accepted: 30 May 2020 / Published: 2 June 2020
(This article belongs to the Section Cancer Vaccines and Immunotherapy)
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. View Full-Text
Keywords: dendritic cells; cancer vaccines; immunotherapy; proteomics; immunopeptidomics dendritic cells; cancer vaccines; immunotherapy; proteomics; immunopeptidomics
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Graciotti, M.; Marino, F.; Pak, H.; Baumgaertner, P.; Thierry, A.-C.; Chiffelle, J.; Perez, M.A.S.; Zoete, V.; Harari, A.; Bassani-Sternberg, M.; Kandalaft, L.E. Deciphering the Mechanisms of Improved Immunogenicity of Hypochlorous Acid-Treated Antigens in Anti-Cancer Dendritic Cell-Based Vaccines. Vaccines 2020, 8, 271.

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