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.

A systematic review on the effects of direct oral anticoagulants on cancer growth and metastasis in animal models

“…Subsequently, full-text version of all abstracts were retrieved to assess whether inclusion criteria were met for inclusion in the qualitative assessment. To include also the most recent studies, the search strategy was repeated in PubMed and EMBASE on the 7th of October 2019, yielding three additional records with a publication date in 2019 [23][24][25].…”

“…n.descr., not described in paper; no., number; i.p., intraperitoneal; i.v., intravenous; s.c., subcutaneous. [29][30][31][32], two studies reported on rivaroxaban (both 2019) [24,25], and one study reported on both dabigatran etexilate and rivaroxaban (2019) [23].…”

“…The 9 selected publications included a total of 19 in vivo experiments (Table 1). Experiments were conducted in mice (n = 18) or rats (n = 1) of both male and female sex; and included carcinogenicity studies [28], spontaneous breast cancer [24], subcutaneous (fibrosarcoma [24], colorectal [24] and pancreatic cancer [25]), orthotopic (pancreatic [28,32] and breast cancer [29,31,23]) and experimental metastasis models (melanoma [27] and ovarian cancer [30]). The number of animals per treatment group ranged from 4 to 50.…”

“…The last threeand most recently publishedpapers describe the effects of rivaroxaban, one of the two DOACs that were recently recommended in clinical guidelines for the use in cancer patients [16]. Graf et al used a syngeneic model in which T241 fibrosarcoma cells were subcutaneously injected in mice which were 14 days later randomized for rivaroxaban treatment (0.4 mg/g chow diet) [24]. Eight days of rivaroxaban treatment resulted in a ± 50% reduction in tumor weight and a ± 70% reduction in the number of macroscopic lung metastases [24].…”

“…Graf et al used a syngeneic model in which T241 fibrosarcoma cells were subcutaneously injected in mice which were 14 days later randomized for rivaroxaban treatment (0.4 mg/g chow diet) [24]. Eight days of rivaroxaban treatment resulted in a ± 50% reduction in tumor weight and a ± 70% reduction in the number of macroscopic lung metastases [24]. When in a follow-up experiment mice were randomized 19 days after tumor cell injection for treatment, rivaroxaban treatment resulted in a trend towards ± 30% inhibition in tumor volume [24].…”