Claudin-12 deficiency inhibits tumor growth by impairing transendothelial migration of myeloid-derived suppressor cells

Migration of myeloid-derived suppressor cells (MDSCs) out of the circulation, across vascular walls, and into tumor is crucial for their immunosuppressive activity. A deeper understanding of critical junctional molecules and the regulatory mechanisms that mediate the extravasation of MDSCs could identify approaches to overcome cancer immunosuppression. In this study we used mice deficient in tight-junction protein Claudin-12 (Cldn12) compared to wild-type mice and found that loss of host Cldn12 inhibited the growth of transplanted tumors, reduced intratumoral accumulation of MDSCs, increased anti-tumor immune responses, and decreased tumor vescular density. Further studies revealed that Cldn12 expression on the cell surface of both MDSCs and endothelial cells is required for MDSCs transit across tumor vascular endothelial cells (ECs). Importantly, expression of Cldn12 in MDSCs was modulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) in an AKT-dependent manner. Therefore, our results indicate that Cldn12 could serve as a promising target for restoring the anti-tumor response by interfering with MDSCs transendothelial migration.