Neutrophil extracellular traps arm DC vaccination against NPM-mutant myeloproliferation

  1. Claudio Tripodo
  2. Barbara Bassani
  3. Elena Jachetti
  4. Valeria Cancila
  5. Claudia Chiodoni
  6. Paola Portararo
  7. Laura Botti
  8. Cesare Vaenti
  9. Milena Perrone
  10. Maurilio Ponzoni
  11. PAtrizia Comoli
  12. Mara Lecchi
  13. Paolo Verderio
  14. Antonio Curti
  15. Mario P Colombo
  16. Sabina Sangaletti  Is a corresponding author
  1. University of Palermo, Italy
  2. Fondazione IRCCS Istituto Nazionale dei Tumori, Italy
  3. University of Palermo School of Medicine Palermo, Italy
  4. IRCCS San RAffaele Scientific Institute, Italy
  5. IRCCS Policlinico San Matteo, Italy
  6. 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

Article and author information

Author details

  1. Claudio Tripodo

    Tumor Immunology Unit, Department of Health Sciences, School of Medicine., University of Palermo, Palermo, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0821-6231
  2. Barbara Bassani

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  3. Elena Jachetti

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Valeria Cancila

    Department of Health Sciences, University of Palermo School of Medicine Palermo, Palermo, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Claudia Chiodoni

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Paola Portararo

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Laura Botti

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Cesare Vaenti

    Tumor Immunology Unit, Department of Health Sciences, School of Medicine., University of Palermo, Palermo, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Milena Perrone

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Maurilio Ponzoni

    IRCCS San RAffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  11. PAtrizia Comoli

    IRCCS Policlinico San Matteo, Pavia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  12. Mara Lecchi

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  13. Paolo Verderio

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  14. Antonio Curti

    Institute of Hematology Seragnoli"", Bologna, Italy
    Competing interests
    The authors declare that no competing interests exist.
  15. Mario P Colombo

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  16. Sabina Sangaletti

    Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
    For correspondence
    sabina.sangaletti@istitutotumori.mi.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7047-287X

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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  1. Claudio Tripodo
  2. Barbara Bassani
  3. Elena Jachetti
  4. Valeria Cancila
  5. Claudia Chiodoni
  6. Paola Portararo
  7. Laura Botti
  8. Cesare Vaenti
  9. Milena Perrone
  10. Maurilio Ponzoni
  11. PAtrizia Comoli
  12. Mara Lecchi
  13. Paolo Verderio
  14. Antonio Curti
  15. Mario P Colombo
  16. Sabina Sangaletti
(2022)
Neutrophil extracellular traps arm DC vaccination against NPM-mutant myeloproliferation
eLife 11:e69257.
https://doi.org/10.7554/eLife.69257

Share this article

https://doi.org/10.7554/eLife.69257

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