TNF Receptor-2 Drives Tumoural Coagulation Factor Synthesis and Enhances Thrombosis in Clear Cell Renal Cell Carcinoma.

Abstract

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 tumours 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, γ), across tumour cells, vascular endothelial cells and T cells is significantly enhanced in ccRCC tumours compared to adjacent normal kidney tissue. Elevated intratumoural protein expression of factors X and V is accompanied by local thrombin generation, fibrin deposition, and the presence of intravascular microthrombi, which themselves harbour coagulation transcripts. Mechanistic analysis using ccRCC organ cultures reveal that selective engagement of tumour 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 tumour cells, endothelial cells, and T cells compared to adjacent normal kidney cultures, whereas TNFR2 knockdown attenuates this response. In addition, TNFR2 appears to link inflammatory signalling with activation of the local coagulation system through the PI3K/Akt/MEK/NFκB signalling axes. These data provide evidence that locally produced coagulation factors driven by TNFR2 signalling may contribute to intratumoural pro-thrombotic outcomes in ccRCC, highlighting a novel pathway with potential therapeutic relevance.