The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity.

The DNA exonuclease three-prime repair exonuclease 1 (TREX1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. As tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here, we show that in tumor cells, TREX1 restricts spontaneous activation of the cGAS/STING pathway, and the subsequent induction of a type I IFN response. As a result, TREX1 deficiency compromised in vivo tumor growth in mice. This delay in tumor growth depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression. Mechanistically, we show that tumor TREX1 loss drove activation of CD8+ T cells and NK cells, prevented CD8+ T-cell exhaustion, and remodeled an immunosuppressive myeloid compartment. Consequently, TREX1 deficiency combined with T-cell-directed immune checkpoint blockade. Collectively, we conclude that TREX1 is essential to limit tumor immunogenicity, and that targeting this innate immune checkpoint remodels the tumor microenvironment and enhances antitumor immunity by itself and in combination with T-cell-targeted therapies. See related article by Toufektchan et al., p. 673.

Lim J ，Rodriguez R ，Williams K ，Silva J ，Gutierrez AG ，Tyler P ，Baharom F ，Sun T ，Lin E ，Martin S ，Kayser BD ，Johnston RJ ，Mellman I ，Delamarre L ，West NR ，Müller S ，Qu Y ，Heger K ... -  《-》

Intratumoral TREX1 Induction Promotes Immune Evasion by Limiting Type I IFN.

Chromosomal instability is a hallmark of human cancer that is associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking a cGAS-STING immune response through the accumulation of cytosolic DNA. The mechanisms of how tumors benefit from chromosomal instability while mitigating associated risks, such as enhanced immune surveillance, are poorly understood. Here, we identify cGAS-STING-dependent upregulation of the nuclease TREX1 as an adaptive, negative feedback mechanism that promotes immune evasion through digestion of cytosolic DNA. TREX1 loss diminishes tumor growth, prolongs survival of host animals, increases tumor immune infiltration, and potentiates response to immune checkpoint blockade selectively in tumors capable of mounting a type I IFN response downstream of STING. Together, these data demonstrate that TREX1 induction shields chromosomally unstable tumors from immune surveillance by dampening type I IFN production and suggest that TREX1 inhibitors might be used to selectively target tumors that have retained the inherent ability to mount an IFN response downstream of STING. See related article by Lim et al., p. 663.

Toufektchan E ，Dananberg A ，Striepen J ，Hickling JH ，Shim A ，Chen Y ，Nichols A ，Duran Paez MA ，Mohr L ，Bakhoum SF ，Maciejowski J ... -  《-》

TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity.

Tani T ，Mathsyaraja H ，Campisi M ，Li ZH ，Haratani K ，Fahey CG ，Ota K ，Mahadevan NR ，Shi Y ，Saito S ，Mizuno K ，Thai TC ，Sasaki N ，Homme M ，Yusuf CFB ，Kashishian A ，Panchal J ，Wang M ，Wolf BJ ，Barbie TU ，Paweletz CP ，Gokhale PC ，Liu D ，Uppaluri R ，Kitajima S ，Cain J ，Barbie DA ... -  《-》

TREX1 as a Novel Immunotherapeutic Target.

Mutations in the TREX1 3' → 5' exonuclease are associated with a spectrum of autoimmune disease phenotypes in humans and mice. Failure to degrade DNA activates the cGAS-STING DNA-sensing pathway signaling a type-I interferon (IFN) response that ultimately drives immune system activation. TREX1 and the cGAS-STING DNA-sensing pathway have also been implicated in the tumor microenvironment, where TREX1 is proposed to degrade tumor-derived DNA that would otherwise activate cGAS-STING. If tumor-derived DNA were not degraded, the cGAS-STING pathway would be activated to promote IFN-dependent antitumor immunity. Thus, we hypothesize TREX1 exonuclease inhibition as a novel immunotherapeutic strategy. We present data demonstrating antitumor immunity in the TREX1 D18N mouse model and discuss theory surrounding the best strategy for TREX1 inhibition. Potential complications of TREX1 inhibition as a therapeutic strategy are also discussed.

Hemphill WO ，Simpson SR ，Liu M ，Salsbury FR Jr ，Hollis T ，Grayson JM ，Perrino FW ... -  《Frontiers in Immunology》

Carboplatin activates the cGAS-STING pathway by upregulating the TREX-1 (three prime repair exonuclease 1) expression in human melanoma.

Ma Z ，Xiong Q ，Xia H ，Liu W ，Dai S ，Cai S ，Zhu Z ，Yan X ... -  《-》