Matrix-Targeting Immunotherapy Controls Tumor Growth and Spread by Switching Macrophage Phenotype

• Published in: Cancer immunology research 2020-03, Vol.8 (3), p.368-382
• Main Authors: Deligne, Claire, Murdamoothoo, Devadarssen, Gammage, Anís N, Gschwandtner, Martha, Erne, William, Loustau, Thomas, Marzeda, Anna M, Carapito, Raphael, Paul, Nicodème, Velazquez-Quesada, Inés, Mazzier, Imogen, Sun, Zhen, Orend, Gertraud, Midwood, Kim S
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Immunological - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Extracellular Matrix - drug effects; Extracellular Matrix - immunology; Female; Human health and pathology; Humans; Immunologic Surveillance; Immunotherapy - methods; Life Sciences; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages - drug effects; Macrophages - immunology; Mice; Phenotype; Tenascin - immunology; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.cir-19-0276

The interplay between cancer cells and immune cells is a key determinant of tumor survival. Here, we uncovered how tumors exploit the immunomodulatory properties of the extracellular matrix to create a microenvironment that enables their escape from immune surveillance. Using orthotopic grafting of mammary tumor cells in immunocompetent mice and autochthonous models of breast cancer, we discovered how tenascin-C, a matrix molecule absent from most healthy adult tissues but expressed at high levels and associated with poor patient prognosis in many solid cancers, controls the immune status of the tumor microenvironment. We found that, although host-derived tenascin-C promoted immunity via recruitment of proinflammatory, antitumoral macrophages, tumor-derived tenascin-C subverted host defense by polarizing tumor-associated macrophages toward a pathogenic, immune-suppressive phenotype. Therapeutic monoclonal antibodies that blocked tenascin-C activation of Toll-like receptor 4 reversed this phenotypic switch and reduced tumor growth and lung metastasis , providing enhanced benefit in combination with anti-PD-L1 over either treatment alone. Combined tenascin-C:macrophage gene-expression signatures delineated a significant survival benefit in people with breast cancer. These data revealed a new approach to targeting tumor-specific macrophage polarization that may be effective in controlling the growth and spread of breast tumors.