Systemic Inactivation of TREX1 Induces Selective Inflammation of the Tumor Microenvironment and Invigorated T Cell-Mediated Tumor Control

Abstract Therapeutic innate immune stimulation within the tumor microenvironment can potentiate endogenous antitumor T cell immunity. Strategies for controlled activation of cGAS/STING signaling are currently under intense investigation. DNase 3’-repair exonuclease 1 (TREX1) is essential for cellular DNA disposal, which prevents autoimmunity ensuing from cGAS/STING activation by endogenous DNA. TREX1-deficient tumor cells elicit enhanced protective immunity in syngeneic models. Here, we showed that induced inactivation of the Trex1 gene in host (non-cancer) cells yields improved type I IFN- and T cell-dependent control of established TREX1-competent tumors. Host TREX1 deficiency was well tolerated and triggered selective immune cell infiltration into tumors but not into other tissues. Induced systemic loss of TREX1 in tumor-bearing mice resulted in enhanced intra-tumoral T cell proliferation and massive increase in numbers of effector and effector-like ‘exhausted’ cells, enabling complete rejection in combination with checkpoint inhibition. To conclude, systemic TREX1 inhibition is a promising approach to boost anti-tumor immunity and to overcome immune evasion mediated by cancer cell-intrinsic cGAS/STING inactivation.