Abstract 5370: Tumor-intrinsic cGAS-STING activation promotes anti-tumor inflammatory response in osteosarcoma

Abstract

Abstract A “cold” tumor microenvironment (TME) is often seen in patients with osteosarcoma (OS). Genomic instability, characteristic of OS, can stimulate the cGAS-STING pathway and activate the innate immune system. Tumor-intrinsic STING pathway silencing mechanisms can link genomic instability to immune evasion in OS. We hypothesize that dysregulation of the cGAS-STING pathway suppresses an innate immune response to genomic instability and plays a key role in tumor progression through establishing an immunosuppressive TME in OS. Using a novel panel of 11 OS patient-derived cell lines, we have identified two groups in terms of capacity for tumor-intrinsic STING activation, and we aim to unravel the mechanism of STING repression in a subset of OS tumors. To investigate the effects of tumor-intrinsic STING activation on macrophage polarization we employed tumor conditioned media (TCM) assays with murine-derived macrophages and tumor lines treated with cGAS-STING agonism. Tumor-intrinsic STING activation resulted in a significant increase in pro-inflammatory macrophages in a manner dependent on tumor STING. Lastly, we performed bulk RNA seq of OS PDX cell lines treated with STING agonist, defining for the first time the OS-specific STING activation signature. We then evaluated primary patient samples for evidence of this signature by single sample GSEA and performed survival analysis after stratifying samples as high or low for this signature, which demonstrated a significant protective effect of the STING activation signature on progression-free and overall survival. We have defined two subtypes of OS in terms of responsiveness to STING activation and demonstrated that STING activation has a protective effect in the human disease, which is the foundation of current efforts to identify targetable mechanism to reverse STING unresponsiveness and activate immune surveillance in this cancer. Citation Format: Elizabeth "Betsy" Peale Young, Christine Johnson, Alex G. Lee, Eric Alejandro Sweet-Cordero. Tumor-intrinsic cGAS-STING activation promotes anti-tumor inflammatory response in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5370.