Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis

E. H. Puttock, E. J. Tyler, M. Manni, E. Maniati, C. Butterworth, M. Burger Ramos, E. Peerani, P. Hirani, V. Gauthier, Y. Liu, G. Maniscalco, V. Rajeeve, P. Cutillas, C. Trevisan, M. Pozzobon, M. Lockley, J. Rastrick, H. Läubli, A. White and O. M. T. Pearce ()
Additional contact information
E. H. Puttock: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
E. J. Tyler: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
M. Manni: University Hospital Basel
E. Maniati: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
C. Butterworth: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
M. Burger Ramos: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
E. Peerani: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
P. Hirani: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
V. Gauthier: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
Y. Liu: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
G. Maniscalco: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
V. Rajeeve: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
P. Cutillas: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
C. Trevisan: University of Padova and Fondazione Istituto di Ricerca Pediatrica Città della Speranza
M. Pozzobon: University of Padova and Fondazione Istituto di Ricerca Pediatrica Città della Speranza
M. Lockley: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre
J. Rastrick: UCB Pharma Ltd
H. Läubli: University Hospital Basel
A. White: UCB Pharma Ltd
O. M. T. Pearce: Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

Date: 2023
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DOI: 10.1038/s41467-023-38093-5

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