Neutrophil extracellular traps arm DC vaccination against NPM-mutant myeloproliferation
- University of Palermo, Italy
- Fondazione IRCCS Istituto Nazionale dei Tumori, Italy
- University of Palermo School of Medicine Palermo, Italy
- IRCCS San RAffaele Scientific Institute, Italy
- IRCCS Policlinico San Matteo, Italy
- Institute of Hematology Seragnoli"", Italy
Abstract
Neutrophil extracellular traps (NET) are web-like chromatin structures composed by dsDNA and histones, decorated with anti-microbial proteins. Their interaction with dendritic cells (DC) allows DC activation and maturation toward presentation of NET-associated antigens. Differently from other types of cell death that imply protein denaturation, NETosis preserves the proteins localized onto the DNA threads for proper enzymatic activity and conformational status, including immunogenic epitopes. Besides neutrophils, leukemic cells can release extracellular traps displaying leukemia-associated antigens, prototypically mutant nucleophosmin (NPMc+) that upon mutation translocates from nucleolus to the cytoplasm localizing onto NET threads. We tested NPMc+ immunogenicity through a NET/DC vaccine to treat NPMc-driven myeloproliferation in transgenic and transplantable models. Vaccination with DC loaded with NPMc+ NET (NPMc+ NET/DC) reduced myeloproliferation in transgenic mice, favoring the development of antibodies to mutant NPMc and and the induction of a CD8+ T cell response. The efficacy of this vaccine was also tested in mixed NPMc/WT bone marrow chimeras in a competitive bone marrow transplantation setting, where the NPMc+ NET/DC vaccination impaired the expansion of NPMc+ in favor of WT myeloid compartment. NPMc+ NET/DC vaccination also achieved control of an aggressive leukemia transduced with mutant NPMc, effectively inducing an anti-leukemia CD8 T cell memory response.
Data availability
All data generated or analyzed during this study are included in the manuscript . Source data will be made available at Open Science Framework for accepted manuscripts
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Author details
Funding
Associazione Italiana per la Ricerca sul Cancro (22204)
- Sabina Sangaletti
Ministero della Salute (GR-2013-02355637)
- Sabina Sangaletti
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments involving animalsdescribed in this study were approved by the Ministry of Health (authorization number 443/2016-PR e 693/2018-PR)
Copyright
© 2022, Tripodo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Neutrophil extracellular traps arm DC vaccination against NPM-mutant myeloproliferation
eLife 11:e69257.
https://doi.org/10.7554/eLife.69257
