Abstract
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.
Highlights
In tumor studies, the contralateral and draining lymph nodes were isolated
Compounds were added at various concentrations as DMSO solutions to the reaction mixture prior to enzyme addition, and final DMSO-vehicle concentration is 2.5% in all exonuclease experiments
To determine which cells were essential for enhanced clearance in D18N mice, we depleted CD4+ or CD8+ T cells by administering 1500 μg of antibody (BioXCell) for 3 days prior to and during tumor challenge (-2, 0, + 2, i.p.)
Summary
Three-prime Repair EXonuclease 1 (TREX1) is a nonprocessive 3’ ! 5’ exonuclease [1]. Biochemical investigations of TREX1 established similar degradation activities using ss- and dsDNA substrates, with some preference for dsDNA with 3’-mismatches and 3’-overhangs. Studies to date support a model where deficiency in TREX1 exonuclease activity leads to accumulation of TREX1 DNA substrate(s), which stimulate the cGAS-STING pathway and promote pathology via subsequent type-I IFN signaling. Another study using microRNAbased TREX1-knockdown successfully demonstrated tumor regression in vivo [89], and in two additional studies it was shown that microRNA-based TREX1-knockdown generates an IFN signature in uninfected wild-type cells [see control data in refs [90, 91]] Interpretation of these data is complicated by the complete loss of TREX1, including the TREX1 C-terminal region not required for exonuclease activity. We tested the anti-cancer therapeutic potential of abolishing TREX1 exonuclease activity using the genetically precise TREX1D18N mice (D18N mice), that express the mouse TREX1 D18N allele from its endogenous promoter that controls the level of expression in the appropriate genomic context. These studies support enhanced tumor immunity in the D18N mice, and TREX1 inhibition as a viable anticancer immunotherapeutic strategy
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