Abstract A057: Therapeutic modality, antitumor efficacy and immune safety for targeting innate immune checkpoint TREX1 as cancer immunotherapy

Abstract Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cGAS-STING pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I interferon (IFN-I)-mediated antitumor response. How TREX1 can be targeted for cancer immunotherapy remains elusive. Here, we report a high-throughput small-molecule inhibitor (SMI) screen of TREX1 using a cell-free DNase assay. We identify two lead compounds that inhibit TREX1 DNase activity at low micromolar concentrations, induce IFN-I signaling in cancer cells, and inhibit tumor growth in mice in an IFNAR-dependent manner. We further show that Trex1 knockout cancer cells elicit robust systemic antitumor immunity through tumor-intrinsic cGAS-STING activation and can be used as autologous cancer vaccines to protect against future tumor challenge. We also establish an inducible whole-body Trex1 knockout mouse model to simulate “on-demand” systemic TREX1 inactivation in adult mice. Sustained TREX1 loss in adult mice suppresses a broad range of solid tumors and metastatic tumors without incurring immune toxicity, demonstrating feasibility of an immune-safe therapeutic window. Together, our data present multiple therapeutic modalities for targeting TREX1 using SMIs and as an autologous cancer vaccine, as well as antitumor efficacy and immune safety, which should pave the way for developing TREX1-targeted cancer immunotherapy. Citation Format: Cong Xing, Xintao Tu, Wanwan Huai, Zhen Tang1, Kun Song, Kennady Knox, Nicole Dobbs, Kun Yang, Nan Yan. Therapeutic modality, antitumor efficacy and immune safety for targeting innate immune checkpoint TREX1 as cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A057.