Abstract LB549: LncRNA PCAT1 activates SOX2 and suppresses radioimmune responses via regulating cGAS/STING signaling in non-small cell lung cancer

Abstract Background: The long non-coding RNA (lncRNA) PCAT1 is upregulated in non-small cell lung cancer (NSCLC), and promotes tumor growth and metastasis, but its roles in the radioimmune responses remain unknown. We aimed to investigate the impacts of PCAT1 on tumorigenesis and radioimmune responses and the underlying molecular mechanisms in NSCLC. Methods: Comprehensive bioinformatics analysis was performed to identify immunosuppressive lncRNAs involved with tumor invasion in NSCLC. The expression levels of PCAT1 were analyzed by in situ hybridization in 55 paired NSCLC and adjacent normal tissues. Both loss- and gain-of-function assays were performed to evaluate the functions of PCAT1 and SOX2 in NSCLC cell behaviors in vivo and in vitro. Bioinformatic analyses, chromatin isolation by RNA purification and dual-luciferase reporter assays were applied to validate the regulatory effects of PCAT1 on SOX2 expression. Chromatin immunoprecipitation, luciferase, and rescue assays were utilized to identify the relationship between SOX2 and the cGAS/STING signaling. Results: PCAT1 was immunosuppressive and related with NSCLC invasion. Increased PCAT1 was negatively correlated with immune cell infiltration in NSCLC. PCAT1 knockdown restrained proliferation, increased apoptosis, and inhibited cell migration and invasion in vivo and in vitro. PCAT1 activated SOX2 that accelerated tumorigenesis and immunosuppression. SOX2 promoted tumor growth through inhibiting cytotoxic T cell immunity. Moreover, SOX2 restrained cGAS transcription and hampered downstream type I IFN-induced immune responses. Inhibition of PCAT1/SOX2 in collaboration with radiation further inhibited tumor growth, and activated the cGAS/STING signaling pathway, which enhanced the immune responses of radiotherapy in NSCLC. Conclusions: PCAT1/SOX2 axis promoted tumorigenesis and immunosuppression through inhibition of cGAS/STING signaling-mediated T-cell activation. Inhibition of PCAT1 and SOX2 synergized with radiotherapy to activate the immune response and could serve as potential therapeutic targets. Citation Format: Yanping Gao, Nannan Zhang, Yan Gong, Conghua Xie. LncRNA PCAT1 activates SOX2 and suppresses radioimmune responses via regulating cGAS/STING signaling in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB549.