Tumor Necrosis Factor Receptor-2 Drives Tumoral Coagulation Factor Synthesis and Enhances Thrombosis in Clear-Cell Renal Cell Carcinoma

Clear-cell renal cell carcinoma (ccRCC), the most prevalent form of kidney cancer, is associated with an increased risk of local and systemic thromboembolism and a worse prognosis. The mechanisms that drive the coagulation program in tumors are not known. Combining RNAscope with immunofluorescence, local transcription of the key coagulation factors X and V, as well as prothrombin and fibrinogen chains (α, β, and γ), across tumor cells, vascular endothelial cells, and T cells is significantly enhanced in ccRCC tumors compared with adjacent normal kidney tissue. Elevated intratumoral protein expression of factors X and V is accompanied by local thrombin generation, fibrin deposition, and the presence of intravascular microthrombi, which themselves harbor coagulation transcripts. Mechanistic analysis using ccRCC organ cultures reveals that selective engagement of tumor necrosis factor receptor-2 (TNFR2) by a R2TNF mutein is sufficient to significantly enhance the transcription and protein expression of the same coagulation program in tumor cells, endothelial cells, and T cells compared with adjacent normal kidney cultures, whereas TNFR2 knockdown attenuates this response. In addition, TNFR2 appears to link inflammatory signaling with activation of the local coagulation system through the phosphatidylinositol 3-kinase/Akt/MEK/NF-κB signaling axes. These data provide evidence that locally produced coagulation factors driven by TNFR2 signaling may contribute to intratumoral prothrombotic outcomes in ccRCC, highlighting a novel pathway with potential therapeutic relevance.