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

Although remodelling of the extracellular matrix (ECM) is associated with the establishment of an immunosuppressive tumour microenvironment, whether the ECM can educate tumor-associated macrophage phenotypes is not known. Here, the authors examine this question using decellularized tissue models of omental metastasis from patient biopsies. 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.

Automated summary

This study demonstrates that the extracellular matrix (ECM) can influence the phenotype of tumor-associated macrophages (TAMs). It reveals an association between the composition of tumor ECM, a specific TAM population, and poor prognosis. By developing a decellularized tissue model, the authors show that the ECM can induce transcriptional profiles in macrophages similar to those found in human tissue. The findings suggest that targeting the tumor ECM in cancer therapies may improve macrophage phenotype and their regulation of immunity.