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

Abstract

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.

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

“…Apart from T cells, other immune cells can be subjected to regulation by the ECM. For instance, recent crosstalk between tumor-associated macrophages and ECM have been reported (51).…”

Macrophages and Extracellular Matrix in Breast Cancer: Partners in Crime or Protective Allies?

“…For example, using an orthotopic mammary tumor model, in which grafted tumor cells were engineered to express high or low levels of tenascin-C, we observed not only more numerous TAM in tenascin-C high tumors, but that TAM were exclusively present inside “tracks” formed by tenascin-C deposition. Treatment of mice with function blocking anti-tenascin-C antibodies caused TAM to accumulate at the edge of the tumor, compared to higher numbers within the tumor stroma in untreated mice ( Figure 2 ) ( 31 ). These data indicate the capacity of ECM molecules to promote TAM infiltration during tumorigenesis, and demonstrate a role for the tumor specific-matrix in controlling the spatial positioning of TAM once within the TME.…”

“…For example, the fibrinogen-like globe (FBG) domain of tenascin-C was identified more than 10 years ago as a ligand of TLR4, and is able to engage aberrant inflammatory responses in TLR4-expressing myeloid cells via the release of TNFα, IL-6, and IL-8 ( 58 ), that are distinct from LPS-dependent responses ( 59 ), prolonging inflammation in arthritis models. Recently, we used an orthotopic grafting murine model of breast cancer to demonstrate that the tumor-derived tenascin-C is able to switch the phenotype of TAM towards a M2-like, pro-tumoral polarization, in a FBG/TLR4 dependent fashion ( 31 ). The triggering of this pathway generated a deleterious inflammatory contexture that helped the tumor escape from immune surveillance and supported a pro-metastatic environment, demonstrating a role for the TLR4 engagement by tenascin-C for tumor growth and spread.…”

Cancer Extracellular Matrix Proteins Regulate Tumour Immunity

“…Transcriptomic and proteomic comparisons of cancers and their normal tissue counterparts demonstrate differences in the abundance of both fibrillar collagens and glycoproteins [ 33 , 34 , 35 ]. Although most of the structural proteins within the cancer ECM are deposited by stromal cells, cancer cells contribute some ECM glycoproteins, ECM regulatory proteins and secreted factors [ 36 , 37 , 38 , 39 , 40 ]. Intriguingly, the ECM proteins deposited by cancer cells appear to play a significant role in disease biology, as it is the expression of these proteins that is best aligned with clinical outcome [ 36 , 40 , 41 ].…”