Myeloid cell-synthesized coagulation factor X dampens antitumor immunity.

Abstract

Immune evasion in the tumor microenvironment (TME) is a crucial barrier for effective cancer therapy, and plasticity of innate immune cells may contribute to failures of targeted immunotherapies. Here, we show that rivaroxaban, a direct inhibitor of activated coagulation factor X (FX), promotes antitumor immunity by enhancing infiltration of dendritic cells and cytotoxic T cells at the tumor site. Profiling FX expression in the TME identifies monocytes and macrophages as crucial sources of extravascular FX. By generating mice with immune cells lacking the ability to produce FX, we show that myeloid cell-derived FX plays a pivotal role in promoting tumor immune evasion. In mouse models of cancer, we report that the efficacy of rivaroxaban is comparable with anti-programmed cell death ligand 1 (PD-L1) therapy and that rivaroxaban synergizes with anti-PD-L1 in improving antitumor immunity. Mechanistically, we demonstrate that FXa promotes immune evasion by signaling through protease-activated receptor 2 and that rivaroxaban specifically targets this cell-autonomous signaling pathway to reprogram tumor-associated macrophages. Collectively, our results have uncovered the importance of FX produced in the TME as a regulator of immune cell activation and suggest translational potential of direct oral anticoagulants to remove persisting roadblocks for immunotherapy and provide extravascular benefits in other diseases.

• Authors: Claudine Graf, Petra Wilgenbus, Sven Pagel, Jennifer Pott, Federico Marini, Sabine Reyda, Maki Kitano, Stephan Macher-Göppinger, Hartmut Weiler, Wolfram Ruf
• Journal: Science immunology (Sci Immunol) Vol. 4 Issue 39 (09 20 2019) ISSN: 2470-9468 [Electronic] United States
• PMID: 31541031 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Factor X

Topics

• Animals
• Factor X (immunology)
• Female
• Humans
• Immunotherapy
• Mammary Neoplasms, Animal (immunology, therapy)
• Mice
• Mice, Inbred C57BL
• Myeloid Cells (immunology)