Hemostatic Factors and Tumor Immunity – a Double Edged Sword
Joseph S. Palumbo, M.D.
Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine
Cincinnati, Ohio, U.S.
An impressive and growing body of literature indicates that there is a bidirectional relationship between the immune and hemostatic systems. Immune system components activate hemostasis, leading to bleeding and thrombotic complications, and hemostatic system components serve as key regulators of immune functions. This bidirectional relationship is particularly important in cancer pathogenesis. Numerous studies support the conclusion that hemostatic system–mediated alterations in immune functions are major determinants of cancer progression. Hemostatic system components have been shown to alter the functions of several innate immune cells in a manner that promotes cancer progression, including macrophages, neutrophils, and natural killer (NK) cells. A prime example of this is metastasis. Previous studies from our lab have shown that the platelet/fibrinogen axis limits metastasis by preventing the clearance of newly formed micrometastases by NK cells. Platelets limit NK cell–mediated clearance of micrometastases by elaboration of TGFb1, as well as other mechanisms yet to be defined. Our recent studies suggest that fibrin may also inhibit NK-mediated killing of micrometastases independently of patients by impeding NK cell contact with tumor cells.
Recent studies have shown that the interplay between immunity and hemostasis in cancer progression is not limited to innate immunity. Several studies have shown that hemostatic factors are determinants of adaptive immune clearance of tumor cells. Studies by Wolfram Ruf’s group have shown that factor X (FX) made by tumor-associated macrophages limits adaptive immune clearance of cancer cells by a mechanism linked to FX activation of PAR-2. Matthew Flick’s group has shown that activation of tumor cell–associated PAR-1 results in suppression of CD8+ T-cell clearance of pancreatic cancer cells in a murine model. While these studies suggest that targeting hemostatic factors could improve adaptive tumor immune clearance, previous studies of human and murine T cells have shown that T cells express PARs, and PAR-mediated thrombin signaling promotes T-cell effector functions. Consistent with this, recent data from our lab suggest that thrombin is important in driving adaptive immune clearance of tumor cells under certain conditions. Additional studies are needed to better define the precise mechanisms underlying the cross-talk between hemostatic and immune functions in cancer if we are going to effectively leverage hemostatic system components as targets for cancer therapy.