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Updated: Jun 3, 2026
Transplantation Into the Mouse Ovarian Fat Pad
Published on: September 7, 2016
TNFSF15 Promotes Vascular Normalization and Tertiary Lymphoid Structure Formation in Experimental Ovarian Cancer
Jing-Ying Wang1, Yu-Ying Wang1, Li-Song Zhang1
1State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, and Haihe Laboratory of Cell Ecosystem, Tianjin, China.
Abstract:
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.
Insights
Tumor Necrosis Factor Superfamily-15 (TNFSF15) treatment inhibits ovarian cancer spread and ascites by normalizing vasculature and promoting immune cell infiltration. This enhances tumor responsiveness to immunotherapy.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Ovarian cancer often shows reduced lymphocyte infiltration and poor response to immunotherapy.
- Tumor microenvironment plays a critical role in cancer progression and treatment resistance.
Purpose of the Study:
- To investigate the therapeutic potential of Tumor Necrosis Factor Superfamily-15 (TNFSF15) in a murine model of ovarian cancer.
- To evaluate the effects of TNFSF15 on tumor vascularization, immune cell infiltration, and immunotherapy response.
Main Methods:
- Treatment of ovarian cancer-bearing mice with recombinant TNFSF15.
- Assessment of tumor dissemination, ascites, tumor vasculature (PDGFβ+ pericytes), hypoxia markers (CD133), lymphatic endothelial cells (Lyve-1+), high endothelial venules (PNAd+), and immune cell infiltration.
- Analysis of tertiary lymphoid structures (TLS) formation and expression of TLS-associated cytokines/chemokines.
- Evaluation of tumor response to PD-1 blockade post-TNFSF15 treatment.
Main Results:
- TNFSF15 treatment significantly inhibited peritoneal cancer spread and reduced ascites.
- Vascular normalization was observed, with increased pericyte coverage and decreased CD133 levels.
- Accumulation of lymphatic endothelial cells and high endothelial venules indicated TLS formation.
- TNFSF15 treatment facilitated infiltration of T cells, B cells, macrophages, and dendritic cells, with upregulated TLS-associated factors.
- Enhanced responsiveness to PD-1 blockade was noted in TNFSF15-treated tumors.
Conclusions:
- TNFSF15 promotes vascular normalization and tertiary lymphoid structures (TLS) formation in ovarian cancer.
- TNFSF15 treatment can restore a favorable immune microenvironment, enhancing anti-tumor immunity.
- TNFSF15 represents a potential therapeutic strategy to improve ovarian cancer treatment outcomes, particularly in combination with immunotherapy.
