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TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity
Tetsuo Tani1, Haritha Mathsyaraja2, Marco Campisi1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Discovery
|January 16, 2024
Summary
Inactivating TREX1 enzyme in cancer cells unleashes STING-IFN signaling, enhancing antitumor immunity. This approach sensitizes tumors to immune checkpoint blockade and cell therapies by boosting immunogenicity.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Oncology
Background:
- Cancers often evade immune detection by suppressing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling.
- Therapeutic strategies like STING agonists and epigenetic modifiers can restore antitumor immunity in preclinical cancer models.
Purpose of the Study:
- To investigate the role of three prime exonuclease 1 (TREX1) in regulating STING-IFN signaling within cancer cells.
- To explore the potential of targeting TREX1 to enhance cancer cell immunogenicity and therapeutic responses.
Main Methods:
- Assessed TREX1 expression and its correlation with STING-IFN signaling in cancer cells.
- Utilized TREX1 inactivation in preclinical mouse tumor models.
- Evaluated the impact of TREX1 targeting on immune cell recruitment, NK cell activity, and response to immune checkpoint blockade (ICB).
Main Results:
- Adaptive induction of TREX1 restrains STING-dependent nucleic acid sensing by degrading cytosolic DNA.
- TREX1 expression is upregulated by autocrine IFN and STAT1, preventing STING-IFN signal amplification.
- TREX1 inactivation in cancer cells activates STING-IFN signaling, recruiting T and NK cells, and enhancing sensitivity to IFNγ and ICB.
Conclusions:
- Targeting TREX1 can amplify cancer cell STING-IFN signaling, increasing tumor immunogenicity.
- TREX1 inactivation represents a complementary strategy to sensitize tumors to ICB and cell therapies.
- Modulating TREX1 offers a novel therapeutic avenue for overcoming immune evasion in cancer.
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