Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
- INSERM, France
- INSERM U1016, France
- Institut Cochin - Inserm U1016-CNRS UMR8104-Université Paris Descartes, France
- CRRET laboratory, France
- Medical University of Białystok, Poland
- Polish Academy of Sciences, Poland
- 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.
Data availability
Relevant source data for all figures and supplement figures have been uploaded as Excel files.
Article and author information
Author details
Emmanuel Donnadieu
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.
Reviewing Editor
- Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, France
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).
Version history
- Received: May 7, 2020
- Accepted: June 5, 2021
- Accepted Manuscript published: June 9, 2021 (version 1)
- Version of Record published: June 14, 2021 (version 2)
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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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
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