Using tissue imaging, transcriptional analysis, and machine learning, Fusilier et al. found that immune cell infiltration and localization within established fibrotic tumors could be predicted by the local topography of fibrillar collagens. This topography was controlled by cancer and stromal cell expression of Tcf4, which promoted collagen III deposition, resulted in disorganized fibrillar networks at the tumor periphery, and favored infiltration of T cells and neutrophils. Macrophages repressed this Tcf4 pathway, negatively regulating immune infiltration. Analysis of data from human solid tumors revealed a strong correlation between TCF4, COL3A1, and T cell and neutrophil signatures.
Contributed by Lauren Hitchings
ABSTRACT: During tumorigenesis, the extracellular matrix is extensively remodeled. Whereas the impact of such remodeling on tumor growth and invasion is well described, the consequences on immune infiltration are not well understood. Combining tissue imaging and machine learning, we show that immune cell localization in tumors can be predicted by the local topography of fibrillar collagens. Such topographies are dictated by a fibrotic pathway driven by transcription factor 4 (Tcf4) in both cancer and stromal cells, which promotes collagen III deposition and results in intermingled collagen networks that favor intratumor infiltration of T cells and neutrophils. Macrophages inhibit this pathway, highlighting their key structural role in shaping the tumor extracellular matrix. Reanalysis of data from human solid tumors revealed a strong correlation between TCF4, COL3A1, and T cell and neutrophil signatures. Together, our data identify collagen network topographies as a key regulator of tumor-infiltrating immune cells.
Author Info: (1) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. Universit Paris-Cit, Paris, France. (2) Institut Curie, PSL University, INSERM U932, Immunity
Author Info: (1) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. Universit Paris-Cit, Paris, France. (2) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (3) Institut Curie, Universit PSL, Sorbonne Universit, CNRS UMR168, Physics of Cells and Cancer, Paris, France. (4) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. Institut Curie, Universit PSL, Sorbonne Universit, CNRS UMR168, Physics of Cells and Cancer, Paris, France. (5) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. Universit Paris Cit, INSERM, EFS, BIGR U1134, Team DSIMB, Paris, France. (6) Turku Bioscience Centre, University of Turku and bo Akademi University, Turku, Finland. (7) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (8) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (9) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (10) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (11) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (12) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (13) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (14) IFOM ETS, AIRC Institute of Molecular Oncology, Milan, Italy. Department of Oncology and Hematology-Oncology, Universit degli Studi di Milano, Milan, Italy. (15) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (16) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (17) Pathologie Exprimentale PMDT, Department of Pathology (PATHEX), Institut Curie, Paris, France. (18) Kaer Labs, Nantes, France. (19) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (20) Chimie ParisTech, Universit PSL, CNRS, Institut de Recherche de Chimie Paris, Paris, France. (21) Institut Curie, Universit PSL, Sorbonne Universit, CNRS UMR168, Physics of Cells and Cancer, Paris, France. (22) IFOM ETS, AIRC Institute of Molecular Oncology, Milan, Italy. Department of Oncology and Hematology-Oncology, Universit degli Studi di Milano, Milan, Italy. (23) IFOM ETS, AIRC Institute of Molecular Oncology, Milan, Italy. Department of Oncology and Hematology-Oncology, Universit degli Studi di Milano, Milan, Italy. (24) Universit Paris Cit, INSERM, EFS, BIGR U1134, Team DSIMB, Paris, France. (25) Turku Bioscience Centre, University of Turku and bo Akademi University, Turku, Finland. Department of Life Technologies, University of Turku, Turku, Finland. InFLAMES Research Flagship, University of Turku, Turku, Finland. Western Finnish Cancer Center (FICAN West), University of Turku, Turku, Finland. Foundation for the Finnish Cancer Institute, Tukholmankatu 8, Helsinki, Finland. (26) Institut Curie, Universit PSL, Sorbonne Universit, CNRS UMR168, Physics of Cells and Cancer, Paris, France. (27) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (28) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. Universit Paris Cit, CNRS, Inserm, Institut Cochin, Paris, France. (29) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (30) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France.
