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

eLife

Matteo Ponzo¹  José Courty¹  Ilaria Cascone¹  Robert Bucki²  Piotr Deptula²  Thomas Guilbert³  Gilles Renault³  Sarah Barrin⁴  Emmanuel Donnadieu⁴  Chahrazade Kantari-Mimoun⁴  Lene Vimeux⁴  Alba Nicolas-Boluda⁵  Katarzyna Pogoda⁶  Florence Gazeau⁷  Laura Fouassier⁸  Javier Vaquero⁹ 

[1] CNRS ERL 9215, CRRET laboratory, University of Paris-Est Créteil (UPEC), Paris, France;Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Białystok, Poland;Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France;Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France;Equipe Labellisée Ligue Contre le Cancer, Paris, France;Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, Paris, France;Equipe Labellisée Ligue Contre le Cancer, Paris, France;Laboratoire Matière et Systèmes Complexes (MSC), CNRS, Université de Paris, Paris, France;Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland;Laboratoire Matière et Systèmes Complexes (MSC), CNRS, Université de Paris, Paris, France;Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France;Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France;TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain;LPP (Laboratoire de physique des plasmas, UMR 7648), Sorbonne Université, Centre national de la recherche scientifique (CNRS), Ecole Polytechnique, Paris, France;Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Barcelona, Spain;

关键词: tumor;    extracellular matrix;    T lymphocytes;    immunotherapy;    cell migration;    stiffness;    Mouse;   

DOI  :  10.7554/eLife.58688

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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 five 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, 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.

【 授权许可】

CC BY