Tumors with microsatellite instability upregulate TREX1 to escape antitumor immunity

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• MSI-H/dMMR tumors exhibit high mutation rates and immune activation but still evade immune surveillance.
• The mechanisms by which these tumors escape immune elimination remain poorly understood.

Purpose of the Study:

• To elucidate the role of cytosolic DNA sensing and DNA repair pathways in MSI-H/dMMR tumor immune evasion.
• To investigate the therapeutic potential of targeting these pathways for cancer immunotherapy.

Main Methods:

• Utilized mouse models of MSI-H/dMMR tumors with genetic alterations in DNA repair and immune signaling pathways.
• Assessed tumor growth, immune cell infiltration (specifically CD8+ T cells), and systemic antitumor immunity following genetic or pharmacological interventions.
• Investigated the interplay between cytosolic DNA, the cGAS-STING pathway, and TREX1 activity within tumor cells.

Main Results:

• MSI-H/dMMR tumors accumulate cytosolic double-stranded DNA, activating the cGAS-STING pathway and upregulating TREX1.
• Depletion of TREX1 in these tumors led to tumor rejection in an immunocompetent setting, dependent on CD8+ T cells.
• TREX1 loss amplified cGAS-STING signaling, enhancing CD8+ T cell activation and systemic antitumor immunity.
• Ablating cGAS-STING signaling abrogated the anti-tumor effects of TREX1 deletion.
• Inhibition of TREX1 reduced MSI-H/dMMR tumor growth in vivo.

Conclusions:

• The cGAS-STING-TREX1 axis represents a critical immune escape mechanism in MSI-H/dMMR cancers.
• Targeting TREX1 can enhance anti-tumor immunity by boosting the cGAS-STING pathway and promoting CD8+ T cell responses.
• TREX1 inhibition holds significant clinical potential for improving immunotherapy outcomes in patients with MSI-H/dMMR tumors.