Abstract
Aside from their roles in hemostasis and thrombosis, thrombocytes or platelets also promote tumor growth via immune suppression. However, the extent to which platelet activation shapes the immunosuppressive tumor microenvironment (TME) and whether platelet inhibition can be leveraged to improve checkpoint blockade are unknown. We show in this study that platelet function in mice mediates suppression of CD8+ T cell function within the TME but not in the draining lymph nodes. Tempering platelet activation genetically reduced TGF-β signaling in both immune and nonimmune cells in the TME, enhanced T cell frequency and function, and decreased CD11b+ myeloid cell infiltration in the tumor. Targeting platelet function pharmacologically in tumor-bearing mice with aspirin and clopidogrel in combination with PD-1 blockade improved tumor control. These results suggest that platelet function represents a continuous, supplemental mechanism of immune evasion co-opted by tumors to evade antitumor immunity and offers an attractive target for combination with immunotherapy.