Research ArticleTUMOR IMMUNOLOGY

Myeloid cell–synthesized coagulation factor X dampens antitumor immunity

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Science Immunology  20 Sep 2019:
Vol. 4, Issue 39, eaaw8405
DOI: 10.1126/sciimmunol.aaw8405

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Targeting factor Xa to promote antitumor immunity

Secreted molecules including cytokines regulate immune cell functions in the tumor microenvironment (TME). Here, Graf et al. report that myeloid cells in the TME produce coagulation factor X that dampens antitumor immune responses and that targeted deletion of factor X in myeloid cells impaired tumor growth in multiple mouse tumor models. Further, they show that rivaroxaban, a factor Xa inhibitor that is used in the clinic as an anticoagulant is effective at promoting systemic antitumor immunity in mouse models. The preclinical findings by Graf et al. also make the case for administering rivaroxaban in combination with therapies targeting the programmed cell death protein 1.

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.

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