TREX1 As a Novel Immunotherapeutic Target

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Apr 19

PMID 33868310

Citations 34

Authors

Wayne O Hemphill

Sean R Simpson

Mingyong Liu

Freddie R Salsbury Jr

Thomas Hollis

Jason M Grayson

Fred W Perrino

Affiliations

Soon will be listed here.

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.

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