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

Alba Nicolas-Boluda,Katarzyna Pogoda,Matteo Ponzo,Florence Gazeau,Gilles Renault,Piotr Deptula,Lene Vimeux,José Courty,Emmanuel Donnadieu,Thomas Guilbert,Sarah Barrin,Ilaria Cascone,Robert Bucki,Javier Vaquero,Laura Fouassier,Chahrazade Kantari-Mimoun

doi:10.7554/elife.58688

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.

Highlights

In the last decade, significant progress has been made in the development of T cell-based immunotherapies [1]
As the MMTV-PyMT tumor model is poorly infiltrated in host T cells [44], we investigated the migration of exogenously purified murine-activated peripheral blood T cells (PBT) in the same manner as for the human EGI-1 model
We found that programmed death 1 receptor (PD-1) blockade alone produced a similar increase in T cell 404 motility whereas the combination therapy showed the same effects as treatments alone (Figure 7405 figure supplement 1F). Overall, while extracellular matrix (ECM) and stiffness normalization achieved through lysyl oxidase (LOX) inhibition increases T cell infiltration and migration, this strategy improves the efficacy of anti-PD-1 blockade on tumor growth. 409 410

Summary

Introduction

Significant progress has been made in the development of T cell-based immunotherapies [1]. We aim at filling this gap through a comprehensive investigation of stiffness evolution in several preclinical mouse models of pancreatic, breast, and bile duct carcinomas, presenting different ECM organizations, coupled to dynamic imaging of fresh tumor slices to monitor T cell motility In concert with these imaging biomarkers of both mechanical properties, ECM architecture, and T cell migration, we explored the consequences of altering the ECM by inhibition of the lysyl oxidase (LOX), a copper124 dependent enzyme responsible for the crosslinking of collagen molecules into fibers that has been seen to be overexpressed in many metastatic tumors and responsible for malignant progression [30]. Despite minor effects in primary tumor growth upon LOX inhibition or PD-1 blockade treatment alone, their combination increases effector CD8 T cell accumulation in tumors and significantly delays tumor progression in a pancreatic cancer model. 131 132

Objectives

Results

Conclusion