Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

  1. Alba Nicolas-Boluda
  2. Javier Vaquero
  3. Lene Vimeux
  4. Thomas Guilbert
  5. Sarah Barrin
  6. Chahrazade Kantari-Mimoun
  7. Matteo Ponzo
  8. Gilles Renault
  9. Piotr Deptula
  10. Katarzyna Pogoda
  11. Robert Bucki
  12. Ilaria Cascone
  13. José Courty
  14. Laura Fouassier
  15. Florence Gazeau  Is a corresponding author
  16. Emmanuel Donnadieu  Is a corresponding author
  1. INSERM, France
  2. INSERM U1016, France
  3. Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, France
  4. CRRET laboratory, France
  5. Medical University of Białystok, Poland
  6. Polish Academy of Sciences, Poland
  7. Université de Paris, France

Abstract

Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing 5 preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase (LOX) was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

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Article and author information

Author details

  1. Alba Nicolas-Boluda

    Institut Cochin, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Javier Vaquero

    Centre de Recherche Saint-Antoine, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Lene Vimeux

    INSERM U1016, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Thomas Guilbert

    Cell Biology of Host Pathogens Interactions, Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Sarah Barrin

    Institut Cochin, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Chahrazade Kantari-Mimoun

    Institut Cochin, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Matteo Ponzo

    University of Paris-Est Creteil (UPEC), CRRET laboratory, CRETEIL, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Gilles Renault

    Institut Cochin, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Piotr Deptula

    Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Białystok, Poland
    Competing interests
    The authors declare that no competing interests exist.
  10. Katarzyna Pogoda

    Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland
    Competing interests
    The authors declare that no competing interests exist.
  11. Robert Bucki

    Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Białystok, Poland
    Competing interests
    The authors declare that no competing interests exist.
  12. Ilaria Cascone

    University of Paris-Est Creteil (UPEC), CRRET laboratory, CRETEIL, France
    Competing interests
    The authors declare that no competing interests exist.
  13. José Courty

    University of Paris-Est Creteil (UPEC), CRRET laboratory, CRETEIL, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Laura Fouassier

    Centre de Recherche Saint-Antoine, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6377-5610
  15. Florence Gazeau

    Laboratoire Matière et Systèmes Complexes, Université de Paris, Paris, France
    For correspondence
    florence.gazeau@u-paris.fr
    Competing interests
    The authors declare that no competing interests exist.
  16. Emmanuel Donnadieu

    Institut Cochin, INSERM, Paris, France
    For correspondence
    emmanuel.donnadieu@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4985-7254

Funding

Ligue Contre le Cancer (Equipe labellisée)

  • Alba Nicolas-Boluda
  • Lene Vimeux
  • Sarah Barrin
  • Chahrazade Kantari-Mimoun
  • Emmanuel Donnadieu

Institut National Du Cancer (Program HTE)

  • Alba Nicolas-Boluda
  • Lene Vimeux
  • Sarah Barrin
  • Chahrazade Kantari-Mimoun
  • Emmanuel Donnadieu

European Commission (685795)

  • Florence Gazeau

Agence Nationale de la Recherche (11-IDEX-0004-02)

  • Javier Vaquero

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 animal experiments were performed in agreement with institutional animal use and care regulations after approval by the animal experimentation ethics committee of Paris Descartes University (CEEA 34, 16-063).

Copyright

© 2021, Nicolas-Boluda 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. Alba Nicolas-Boluda
  2. Javier Vaquero
  3. Lene Vimeux
  4. Thomas Guilbert
  5. Sarah Barrin
  6. Chahrazade Kantari-Mimoun
  7. Matteo Ponzo
  8. Gilles Renault
  9. Piotr Deptula
  10. Katarzyna Pogoda
  11. Robert Bucki
  12. Ilaria Cascone
  13. José Courty
  14. Laura Fouassier
  15. Florence Gazeau
  16. Emmanuel Donnadieu
(2021)
Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
eLife 10:e58688.
https://doi.org/10.7554/eLife.58688

Share this article

https://doi.org/10.7554/eLife.58688

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