Background: The extracellular matrix (ECM) is a major component of the tumor microenvironment that interacts with all cells and in particular provides instructions to immune cells. Different therapeutic strategies are being evaluated to restore protective immunity in tumors, however ECM can induce signals that impair immune responses and thus are potential targets for new antitumor strategies.

Methods and results: In TNC knockout mice with tongue tumors, immune cells invaded the tumor nests whereas they accumulated within the matrix of tumors from wild-type mice. By binding to the chemokine CCL21 and enhancing its expression in lymphatic endothelial cells, TNC is able to direct the localization of dendritic cells inside the stroma. TNC also induces the natural receptor of CCL21, named CCR7. Thus, TNC through binding CCL21 retains dendritic cells in the matrix, thus sequestering them away from the tumor cells. Altogether this caused an immune suppressive tumor microenvironment, that we also found to be generated in human head and neck cancer. We discovered that blocking CCR7 inhibited the interaction of the dendritic cells with TNC thus releasing them from the matrix and facilitating their entry into the tumor nests, activating anti-tumor immunity, killing the tumor cells and blocking tumor growth and tumor cell dissemination.
In breast cancer, CD8+ T lymphocytes were found to be trapped in the TNC network with CXCL12 thus enhancing tumor growth and metastasis. The immune suppressive power of TNC has been widely demonstrated as it could be abolished by blocking CXCL12/CXCR4 signaling. The described mechanism is relevant in human as we showed a positive correlation between TNC expression, CXCL12 and stromal CD8+ T lymphocytes trapping, which correlates with worsened survival of breast cancer patients.
Conclusions: TNC is regulating stromal retention of immune cells. Targeting chemoretention by TNC could be valuable for reactivating tumor immunity in cancer patients.