Coagulation signaling and cancer immunotherapy

Area of Science:

• Oncology
• Immunology
• Hematology

Background:

• The hemostatic system interacts with cancer, influencing thrombosis, angiogenesis, and metastasis.
• Platelets, tissue factor pathway, and protease-activated receptors (PARs) are key in immunity.
• Coagulation signaling networks have immune-evasive roles in preclinical tumor models.

Purpose of the Study:

• Investigate the role of coagulation signaling in tumor immune evasion.
• Evaluate FXa inhibitors as a strategy to overcome tumor immune suppression.
• Determine if FXa inhibitors synergize with immunotherapy.

Main Methods:

• Utilized immune-competent preclinical tumor models.
• Examined tumor-type specific PAR1 signaling.
• Assessed FXa-PAR2 signaling in tumor-associated macrophages.
• Administered oral FXa inhibitors and heparin.
• Evaluated effects on macrophage polarization, antigen presentation, and cytotoxic T cell activity.
• Investigated synergy with checkpoint inhibitor therapy.

Main Results:

• PAR1 signaling aids tumor escape from cytotoxic T cells.
• FXa-PAR2 signaling drives pro-tumorigenic macrophage polarization.
• Oral FXa inhibitors reprogram macrophages, boost antigen presentation, and increase tumor-killing T cells.
• Rivaroxaban (oral FXa inhibitor) synergizes with checkpoint inhibitors to enhance antitumor immunity.
• Heparin was ineffective in blocking extravascular coagulation signaling.

Conclusions:

• Targeting FXa-PAR2 signaling with oral FXa inhibitors can reverse tumor immune evasion.
• Antithrombotic therapy with oral FXa inhibitors may enhance clinical outcomes of immunotherapy regimens.
• FXa inhibitors offer a promising strategy to potentiate cancer immunotherapy.