Coagulation proteases modulate nucleic acid uptake and cGAS-STING-IFN induction in the tumor microenvironment

Area of Science:

• Oncology
• Immunology
• Hematology

Background:

• Malignancies involve complex interactions between immune cells, platelets, and coagulation, impacting thrombosis and metastasis.
• Platelets and coagulation factors in the tumor microenvironment (TME) can promote tumor growth and immune suppression.

Purpose of the Study:

• To investigate the role of coagulation factor X (FX) on monocytes in the TME.
• To explore the impact of FXa signaling on immune cells and anti-tumor responses.
• To evaluate FXa inhibition as a potential therapeutic strategy in cancer immunotherapy.

Main Methods:

• Analysis of FX-expressing monocytes and platelet aggregates in cancer patients and tumor-bearing mice.
• Utilizing myeloid cell-specific gene deletion of FX and PAR2 signaling blockade.
• Assessing immune cell function, including antigen uptake and T cell responses, in response to FXa inhibition.
• Investigating the synergy between FXa inhibitors and immune checkpoint inhibitors.

Main Results:

• Increased FX-expressing monocytes form platelet aggregates, suppressing monocyte differentiation and antigen presentation.
• Myeloid cell FXa-PAR2 signaling deficiency enhances APCs and activates the cGAS-STING-IFN-I pathway, expanding exhausted CD8+ T cells.
• Pharmacological FXa blockade expands T cell priming and synergizes with immune checkpoint inhibitors, improving anti-tumor immunity.

Conclusions:

• FXa signaling on myeloid cells in the TME suppresses anti-tumor immune responses.
• Inhibition of FXa can restore immune cell function and enhance anti-tumor immunity.
• FXa inhibition holds translational potential for combination therapy with cancer immunotherapies.