A novel TREX1 inhibitor, VB-85680, upregulates cellular interferon responses

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• The cGAS-STING pathway is crucial for innate immunity against cancer, mediating Type-1 Interferon (IFN) production and T cell priming.
• Cytosolic double-stranded DNA (dsDNA) activates cyclic GMP-AMP synthase (cGAS), which signals STING (STimulator of INterferon Genes) to induce IFN-related gene expression.
• Three-prime Repair EXonuclease 1 (TREX1) degrades cytosolic dsDNA, acting as a negative regulator of the cGAS-STING pathway and reducing IFN secretion.

Purpose of the Study:

• To characterize the activity of VB-85680, a small-molecule inhibitor of TREX1.
• To evaluate the potential of TREX1 inhibition to enhance STING pathway activation and anti-tumor immunity.

Main Methods:

• In vitro enzymatic assays to assess TREX1 inhibition by VB-85680 using human and mouse cell lysates.
• Cell-based assays to measure STING signaling activation and IFN-stimulated gene (ISG) expression in response to VB-85680 treatment.
• Combination studies with exogenous DNA in THP1-Dual™ cells under low-serum conditions.

Main Results:

• VB-85680 effectively inhibited TREX1 exonuclease activity in vitro.
• Treatment with VB-85680 led to the activation of STING signaling and ISG expression in intact cells.
• Combined treatment with VB-85680 and exogenous DNA enhanced the ISG response in THP1-Dual™ cells.

Conclusions:

• VB-85680 is a potent TREX1 inhibitor with the capacity to activate the cGAS-STING pathway.
• TREX1 inhibition holds promise for enhancing anti-tumor immunity, especially in combination with therapies that generate cytosolic DNA.