Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation. Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. We also identify a conserved inflammatory epitope in related proteins from diverse families, and demonstrate that its presence targets molecules for TLR detection, while its absence enables escape of innate immune surveillance. These data reveal a unique molecular code that defines endogenous proteins as inflammatory stimuli by marking them for recognition by TLRs.

To protect against danger, the innate immune system must promptly and accurately sense alarm signals, and mount an appropriate response to restore homeostasis. One endogenous trigger of immunity is tenascin-C, a large hexameric protein of the extracellular matrix. Upregulated upon tissue injury and cellular stress, tenascin-C is expressed during inflammation and tissue remodeling, where it influences cellular behavior by interacting with a multitude of molecular targets, including other matrix components, cell surface proteins, and growth factors. Here, we discuss how these interactions confer upon tenascin-C distinct immunomodulatory capabilities that make this matrix molecule necessary for efficient tissue repair. We also highlight in vivo studies that provide insight into the consequences of misregulated tenascin-C expression on inflammation and fibrosis during a wide range of inflammatory diseases. Finally, we examine how its unique expression pattern and inflammatory actions make tenascin-C a viable target for clinical exploitation in both diagnostic and therapeutic arenas.

The interplay between cancer cells and immune cells is a key determinant of tumor survival. Here, we uncovered how tumors exploit the immuno-modulatory 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 pro-inflammatory, antitumoral macrophages, tumor-derived tenascin-C subverted host defense by polarizing tumor-associated macrophages towards a pathogenic, immune suppressive phenotype. Therapeutic monoclonal antibodies that blocked tenascin-C activation of toll-like receptor 4 reversed this phenotypic switch in vitro and reduced tumor growth and lung metastasis in vivo, providing enhanced benefit in combination with anti-PD-L1 antibodies 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.