PT - JOURNAL ARTICLE AU - Laurent Gros AU - Chiara Ursino AU - Julie Constanzo AU - Nadine Zangger AU - Etienne Meylan AU - Nathalie Bonnefoy AU - Julien Faget TI - Low STING expression in a transplantable Kras<sup>G12D</sup>/P53<sup>ko</sup> lung cancer model contributes to SiglecF<sup>+</sup> neutrophil and CD103<sup>+</sup>Treg accumulation in tumors AID - 10.1101/2021.01.04.425311 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.01.04.425311 4099 - http://biorxiv.org/content/early/2021/01/06/2021.01.04.425311.short 4100 - http://biorxiv.org/content/early/2021/01/06/2021.01.04.425311.full AB - Lung cancer is the leading cause of mortality by cancer worldwide. Non-small cell lung cancer is the most common type of lung cancer and mutations in the KRAS gene are frequently found in this pathology. While immune checkpoint inhibitors are providing new hope for lung cancer care, only a subset of patients show durable benefit from these new therapies designed to drive an efficient anti-tumor immune response. Hence, it is crucial to better understand the mechanisms through which the tumor immune microenvironment is established in lung tumors. Using bioinformatics, we observed that high expression of the STimulator of INterferon Gene (STING) associates with a longer overall survival specifically in KRAS mutant cancer patients. In lung cancer cell lines, STING expression is linked to interferon response and epithelial-to-mesenchymal transition. Because STING activation in immune cells of the tumor microenvironment using specific agonists is an emerging strategy to trigger an anti-tumor immune response, we took advantage of two transplantable models of Kras driven lung cancer, expressing high or low levels of STING, to investigate the function of STING directly in cancer cells in vivo. We observed that high-STING expression and constitutive STING signaling were critical for transplanted tumor formation rather than playing a major role in tumor immunogenicity. Besides, low-STING expression in cancer cells is associated with an immunosuppressive tumor microenvironment characterized by the accumulation of tumor promoting SiglecF+ neutrophils and CD103+ regulatory T cells. In that model, knocking out STING increased the early response to anti-PD1 treatment. We conclude that low-STING expression in cancer cells might confer them an independence from pro-inflammatory signals and a greater immunosuppressive capability and aggressiveness.Competing Interest StatementThe authors have declared no competing interest.CCLEcancer cell line encyclopediacGAScyclic GMP-AMP synthase2’3’-cGAMPcyclic Guanosine(2’,5’)phosphate-Adenosine(3’,5’)phosphateIFNinterferonISGInterferon-stimulated genesIRF3Interferon regulatory factor-3MEFmouse embryonic fibroblastsNSCLCnon-small cell lung cancerPD1programmed cell death receptor-1STINGStimulator of Interferon GeneTBK1Tank-binding kinase-1TCGAthe cancer genome atlas