A balanced coagulation pathway represents an equilibrium between the procoagulant pathway that is responsible for clot formation in response to vessel injury and mechanisms that inhibit clot extension beyond the injury site. Moreover, coagulation also limits infections and is therefore connected with immunity. The protective properties of the coagulation system are exploited by tumor cells to shape the tumor microenvironment (TME). Coagulation protease signaling occurs via protease-activated receptors (PARs) that converge with other innate immune signaling pathways to control dendritic cell and macrophage phenotypes. The targeting of cancer-intrinsic macrophage signaling by anticoagulants may therefore alter anti-tumor immunity. Dr. Claudine Graf of Germany and colleagues hypothesized that anticoagulants with limited tissue penetrance, such as low-molecular-weight heparins (LMWH), may differ from small molecule FXa inhibitors in targeting coagulation protease signaling in the intra-tumoral, extravascular space.
The team had two major aims: (1) to define tumor-promoting coagulation signaling in the TME, and (2) compare the therapeutic efficacy of clinically used anticoagulants in targeting these pathways. Investigators analyzed tumor growth and metastasis in genetically induced or transplanted preclinical tumor models in immunocompetent mice, and characterized changes in immune cells by flow cytometry, mRNA expression profiling, and ELISpot assays. The team demonstrated that PAR2-activation, by macrophage-synthesized coagulation FX, controls the immune-evasive phenotype of tumor-associated macrophages at different stages of tumor progression. Only rivaroxaban attenuated tumor growth in spontaneously developing and transplanted tumor models. As demonstrated by genetic abrogation of FXa-PAR2 signaling, rivaroxaban effectively reprograms macrophage polarization in the TME, activates cross-presenting innate immune cells in tumor-draining lymph nodes, and fosters expansion of tumor-reactive cytotoxic T cells in the TME. Dr. Graf stated, “Our data in different mouse models clearly demonstrates that coagulation innate immune signaling promotes immune-evasion and that tissue-penetrating FXa inhibitors are effective in enhancing anti-tumor immunity. Oral FXa inhibitors may have clinical anti-cancer benefits beyond thrombosis prophylaxis and may even act synergistically with immunotherapy regimens in cancer patients.”