TNFSF15 Promotes Vascular Normalization and Tertiary Lymphoid Structure Formation in Experimental Ovarian Cancer.

Diminished lymphocyte infiltration and activation in ovarian cancer are attributable to the malignancy and irresponsiveness to immunotherapy. We show here that treatment of a murine model of ovarian cancer with recombinant tumor necrosis factor superfamily-15 (TNFSF15) results in a marked inhibition of peritoneal dissemination of the cancer cells and a substantial reduction of ascites. The treatment leads to normalization of the tumor vasculature judged by enhanced coverage of the neo-blood vessels with PDGFβ+ pericytes and diminished levels of the hypoxia-responsive cancer stem cell marker CD133. Additionally, the treatment gives rise to accumulation of Lyve-1+ lymphatic endothelial cells and PNAd+ high endothelial venules (HEV) in the tumors, consistent with the formation of tertiary lymphoid structures (TLS). Moreover, the treatment results in facilitated tumor infiltration of T cells, B cells, macrophages, and dendritic cells, the latter exhibit upregulated expression of TLS-associated cytokines and chemokines, including Lt-α, Lt-β, IFN-β, TNF-α, CCL19, CCL21, CXCL13, and CXCL10. Furthermore, there is an enhanced responsiveness in TNFSF15-treated tumors toward PD-1 blockade treatment. These findings suggest that TNFSF15 is capable of facilitating vascular normalization and TLS formation, and thus promoting a reinstitution of the immune microenvironment in ovarian cancer.