Abstract A005: STING activation overcomes immune escape in osteosarcoma metastasis
Authors: Young Elizabeth "Betsy" , Schott Courtney R. , Sweet-Cordero E. Alejandro 
Published: September 2022

Abstract
Chromosomal instability (CIN) has been known to be a hallmark of cancer for decades, but how CIN influences the tumor microenvironment (TME) and defines the ability of tumors to metastasize is a fundamental question in cancer biology that remains unanswered. Osteosarcoma (OS) is a highly malignant bone tumor characterized by high CIN and an immunosuppressive TME and is thus an excellent model system to address the role of CIN in metastasis and TME programming. The cGAS-STING-ENPP1 pathway links CIN to immune evasion and metastasis, functioning to produce an immune response to infection by sensing cytoplasmic double-stranded DNA (dsDNA) and transducing this signal via the second messenger cGAMP, which activates interferon gene expression. CIN in cancer cells also results in cytosolic dsDNA which can also activate the STING pathway. However, cGAMP can also be hydrolyzed by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which negatively regulates STING activation in the TME, enabling cancer cells to survive CIN and avoid immune surveillance. Our studies of this pathway in human-in-mouse metastasis models of OS indicate that either ENPP1 overexpression (OE) or STING knockout (KO) enhance metastasis, nominating the STING pathway as an important regulator metastasis in OS and suggesting that STING agonists or ENPP1 inhibitors may have therapeutic benefit. Indeed, OS patient-derived xenograft cell lines that are least aggressive in vivo show strong STING activation in response to transfection with dsDNA, while cell lines with a higher metastatic capacity do not, suggesting that metastatic capacity may be directly linked to STING pathway downregulation. Given that a fully competent murine immune system is crucial for evaluation of the STING pathway in mediating antitumor immunity, a major current focus of this work is development and use of syngeneic murine OS models for further in vivo dissection of the role of the STING-ENPP1 axis in OS. Future studies will also evaluate if ENPP1 inhibition constitutes a novel immune-targeted therapeutic that may overcome an immunosuppressive TME and activate the immune system in response to the cell-intrinsic consequences of CIN. Moreover, elucidating the immune cell types that drive STING-mediated anti-tumor immunity will inform new combinatorial approaches together with ENPP1 inhibition. Given the therapeutic relevance of TME reprogramming and the limited success that immunotherapy has garnered in many solid tumors, this line of investigation has broad applicability beyond OS and may enable rational design of novel combination immunotherapies to treat metastatic sarcomas and other CIN-high cancers.
Citation Format: Elizabeth "Betsy" Young, Courtney R. Schott, E. Alejandro Sweet-Cordero. STING activation overcomes immune escape in osteosarcoma metastasis [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A005.