Abstract LB361: The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti-tumor immunity

Abstract The DNA exonuclease TREX1 (Three-prime repair exonuclease 1) 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. Since 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 indeed restricts the 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 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 synergized 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 anti-tumor immunity by itself and in combination with T cell-targeted therapies. Citation Format: Junghyun Lim, Ryan Rodriguez, Katherine Williams, John Silva, Alan Gutierrez, Paul Tyler, Faezzah Baharom, Tao Sun, Eva Lin, Scott Martin, Brandon Kayser, Robert J. Johnston, Ira Mellman, Lélia Delamarre, Nathaniel West, Sören Müller, Yan Qu, Klaus Heger. The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti-tumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB361.