Mammalian Neuraminidase-1 is a Critical Regulator of Platelet-derived Thromboxane A2 (TXA2) T-cell Immunosuppression to Promote Tumor Progression and Metastasis

Abstract

Aspirin or celecoxib in combination with chemotherapy significantly reduced the risk for disease recurrence and improved survival after colorectal cancer surgery in the approximately 20% of patients harbouring activating mutations in the PIK3CA gene1-3. The biological mechanisms behind the anti-cancer effects of these medications are an area of intense research interest. Recently, Yang et al.4 found that platelet-derived thromboxane A2 (TXA2) inhibits T-cell activity through the expression of the guanine exchange factor ARHGEF1, and that aspirin was able to inhibit ARHGEF1 expression and preserve T-cell functionality and cancer immunity by blocking TXA2 production4. TXA2 production is inhibited by the effect of aspirin on cyclooxygenase-1 (COX-1). Celecoxib, a selective COX-2 inhibitor, does not inhibit platelet TXA2 production but has shown almost identical efficacy to aspirin in controlled clinical trials3. Here, we show that the enzyme mammalian neuraminidase 1 (NEU1) is involved in the activation and downstream signaling of the TXA2 receptor (TP) on T cells in response to TXA2. Both aspirin and celecoxib significantly inhibited TXA2-induced NEU1 activity and reduced ARHGEF1 expression. This regulation of the TP receptor by NEU1 may explain why aspirin and celecoxib demonstrated comparable clinical efficacy despite only aspirin being able to inhibit TXA2 synthesis. Targeting NEU1 may provide a novel therapeutic strategy against cancer cell metastasis by preserving a functional T-cell response against cancer.