Institut Curie, Paris, France
Impact of tumor associated macrophages on the biophysical properties of extracellular matrix and associated immune infiltrate
The extracellular matrix constitutes the structural scaffold for organs and tissues and provides key physical and biochemical cues to cells. While the profound remodeling of the ECM during tumorigenesis has been long reported, its effect on anti-tumoral immune responses is still poorly understood. Using an interdisciplinary approach at the frontier of immunology, cell biology and biophysics, we investigated (1) how macrophages, key immune drivers of tumorigenesis, modulate the biophysical properties of the tumoral ECM and, (2) how those ECM changes impact on the anti-tumoral immunity.
We here show that macrophage depletion at late stages of tumorigenesis induced a drastic remodeling of the tumor ECM architecture. We found that the collagen capsula was thickened, disorganized and softer, as assessed by atomic force microscopy. In addition, fiber-rich areas were more frequently observed within the tumor core upon macrophage depletion. Both ECM modifications correlated with a massive T lymphocyte infiltration and were associated to decreased tumor growth. Analysis of the mechanisms underlying these ECM changes by combination of single-cell RNA sequencing and MIIC (Multivariate Information-based Inductive Causation algorithms) pointed to an essential role of the collagen 3/collagen 1 ratio and upstream transcription factor AEBP1. Our study brings fundamental knowledge on how remodeling of the tumor ECM defines its recognition and elimination by the immune system, contributing to the emergence of the nascent field of immunophysics.
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