Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
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Updated: Nov 2, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Alba Nicolas-Boluda1,2,3, Javier Vaquero4,5,6,7, Lene Vimeux1,2
1Institut Cochin, INSERM U1016/CNRS UMR 8104, Université de Paris, 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 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.
Insights
Tumor stiffness, driven by the extracellular matrix (ECM), impedes T cell migration and limits cancer immunotherapy effectiveness. Targeting ECM with lysyl oxidase inhibition improves T cell infiltration and enhances anti-PD-1 therapy efficacy.
Area of Science:
- Oncology
- Immunology
- Biophysics
Background:
- Immune checkpoint inhibitors (ICIs) show limited efficacy in a fraction of cancer patients.
- The dense tumor extracellular matrix (ECM) can act as a physical barrier, hindering T cell infiltration.
- Understanding the interplay between ECM mechanics and anti-tumor immunity is crucial for improving therapeutic outcomes.
Purpose of the Study:
- To investigate the relationship between tumor stiffening, ECM architecture remodeling, and intratumoral T cell migration in preclinical cancer models.
- To evaluate the impact of targeting ECM crosslinking on T cell migration and immunotherapy response.
Main Methods:
- Comparison of five preclinical mouse tumor models with diverse tumor microenvironments.
- In vivo measurement of tumor stiffness and ECM crosslinking.
- Assessment of T cell migration dynamics within tumors.
- Application of an ECM-targeted strategy involving lysyl oxidase inhibition.
Main Results:
- Tumor stiffness strongly correlated with tumor growth and ECM crosslinking.
- Increased tumor stiffness was negatively correlated with intratumoral T cell migration.
- Inhibition of lysyl oxidase reduced ECM content and tumor stiffness.
- Reduced tumor stiffness led to improved T cell migration and enhanced anti-PD-1 blockade efficacy.
Conclusions:
- Mechanical properties of solid tumors, specifically stiffness, are key factors in resistance to immunotherapy.
- Targeting ECM remodeling, by inhibiting collagen stabilization, can enhance T cell infiltration.
- Combining ECM-targeting strategies with anti-PD-1 therapy presents a promising approach to overcome immunotherapy resistance.
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