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

Alba Nicolas-Boluda, Javier Vaquero, Sarah Barrin, Chahrazade Kantari-Mimoun, Matteo Ponzo, Gilles Renault, Piotr Deptuła, Katarzyna Pogoda, Robert Bucki, Ilaria Cascone, Jose Courty, View ORCID ProfileLaura Fouassier, Florence Gazeau, View ORCID ProfileEmmanuel Donnadieu
doi: https://doi.org/10.1101/2020.05.19.104430
Alba Nicolas-Boluda
1Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France
2Laboratoire Matière et Systèmes Complexes (MSC), CNRS-UMR 7057, Université de Paris, Paris, France
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Javier Vaquero
3Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France
4TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
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Sarah Barrin
1Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France
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Chahrazade Kantari-Mimoun
1Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France
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Matteo Ponzo
5CNRS ERL 9215, CRRET laboratory, University of Paris-Est Créteil (UPEC), France
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Gilles Renault
1Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France
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Piotr Deptuła
6Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2C, PL-15222 Białystok, Poland
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Katarzyna Pogoda
7Institute of Nuclear Physics, Polish Academy of Sciences, PL-31342 Kraków, Poland
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Robert Bucki
6Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2C, PL-15222 Białystok, Poland
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Ilaria Cascone
5CNRS ERL 9215, CRRET laboratory, University of Paris-Est Créteil (UPEC), France
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Jose Courty
5CNRS ERL 9215, CRRET laboratory, University of Paris-Est Créteil (UPEC), France
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Laura Fouassier
3Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France
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  • ORCID record for Laura Fouassier
Florence Gazeau
2Laboratoire Matière et Systèmes Complexes (MSC), CNRS-UMR 7057, Université de Paris, Paris, France
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  • For correspondence: emmanuel.donnnadieu@inserm.fr florence.gazeau@u-paris.fr
Emmanuel Donnadieu
1Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France
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  • ORCID record for Emmanuel Donnadieu
  • For correspondence: emmanuel.donnnadieu@inserm.fr florence.gazeau@u-paris.fr
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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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 21, 2020.
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Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
Alba Nicolas-Boluda, Javier Vaquero, Sarah Barrin, Chahrazade Kantari-Mimoun, Matteo Ponzo, Gilles Renault, Piotr Deptuła, Katarzyna Pogoda, Robert Bucki, Ilaria Cascone, Jose Courty, Laura Fouassier, Florence Gazeau, Emmanuel Donnadieu
bioRxiv 2020.05.19.104430; doi: https://doi.org/10.1101/2020.05.19.104430
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Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
Alba Nicolas-Boluda, Javier Vaquero, Sarah Barrin, Chahrazade Kantari-Mimoun, Matteo Ponzo, Gilles Renault, Piotr Deptuła, Katarzyna Pogoda, Robert Bucki, Ilaria Cascone, Jose Courty, Laura Fouassier, Florence Gazeau, Emmanuel Donnadieu
bioRxiv 2020.05.19.104430; doi: https://doi.org/10.1101/2020.05.19.104430

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