Macrophage Factor Xa Signaling Promotes Cancer Immune Evasion

Coagulation signaling through protease activated receptors (PARs) participates in inflammation and immunity. In cancer, tissue factor (TF) driven signaling via PAR2 promotes tumor progression, but effective pharmacological strategies to inhibit the PAR2 activating proteases for clinical anti-cancer benefit are currently unknown. To gain a better understanding of signaling by coagulation proteases, we generated PAR2 mouse strains with mutations that abolish canonical proteolysis by all proteases including FVIIa (PAR2 R38E) or create specific resistance to cleavage by the TF-FVIIa-Xa signaling complex (PAR2 G37I) that requires the endothelial cell protein C receptor (EPCR, Procr). As expected from delayed breast cancer development in PAR2-deficient polyoma middle T (PyMT) mice, cancer progression was impaired in completely cleavage-resistant PAR2 R38E relative to wild-type (WT) mice. In contrast, FXa-resistant PAR2 G37I mice displayed normal tumor initiation, but unexpectedly tumor growth was also markedly attenuated compared to WT mice. A similar reduction in transplanted syngeneic tumor growth in mutant PAR2 R38E and PAR2 G37I mice indicated that impaired FXa-PAR2 signaling in the tumor microenvironment (TME), but not by tumor cells, impaired tumor expansion in FXa-resistant PAR2 G37I mice.Macrophages, but not the studied tumor models, expressed FVII and FX, along with other components of the TF pathway. Tumor-associated macrophage (TAM) phenotypes are determined by complex i...
Source: Blood - Category: Hematology Authors: Tags: 321. Blood Coagulation and Fibrinolytic Factors: The Clotting System in Inflammation, Immunity, and Cancer Source Type: research