Mp05-16 LNC-Pc, a Phase Separation Sustainer, Enhances Anti-Tumor Immunity via the Rna Sensor Pathway

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP05)1 May 2024MP05-16 LNC-PC, A PHASE SEPARATION SUSTAINER, ENHANCES ANTI-TUMOR IMMUNITY VIA THE RNA SENSOR PATHWAY Zean Li, Huang Hai, and Luo Man-Li Zean LiZean Li , Huang HaiHuang Hai , and Luo Man-LiLuo Man-Li View All Author Informationhttps://doi.org/10.1097/01.JU.0001008740.27639.cc.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer is the most frequent cancer in male in the world with low respond rate to immune checkpoint blockade. Tumor infiltrating lymphocytes (TILs) and cytotoxicity effect of immune cell are important factors for the respond rate of immunotherapy. Therefore, it is essential to identify a molecule related to TILs and cytotoxicity effect. In our screening, we found that Lnc-PC is related to immune cell infiltration and cytotoxicity effect of immune cells. However, the mechanism of how Lnc-PC promotes anti-tumor immunity need further study. METHODS: Transcriptome sequencing data of PCa from TCGA were collected to identify lncRNA related to TILs and cytotoxicity effect by analyzing with immune score and ISG score. The function of Lnc-PC was investigated by immune-tumor cells co-culture assays and flow cytometry in vitro. Tumor microenvironment remodeling role of Lnc-PC were further investigated by gain- and loss-of-function assays in immunodeficient and immune competent orthotopic xenograft mice model. The mechanisms of Lnc-PC in regulating RIG-I-Like Receptors (RLRs) were investigated by transcriptome sequencing, RNA-pulldown, RNA co-immunoprecipitation, mass spectrometry and western blot. RESULTS: We discovered an interferon stimulated genes (ISGs) related lncRNA, Lnc-PC, which was related to TILs and cytotoxicity effect positively in prostate cancer. Functional experiments revealed that Lnc-PC increased the expression level of ISGs PD-L1 and MHC class I molecules significantly and the number of CD8+T cells recruited by supernatant of tumor cells. Lnc-PC did not affect tumor growth in vitro or in immunodeficient mice, but in immune competent mice. Flow cytometry analysis showed that the number of CD8+T cells, macrophages and DC, the proportion of activated CD8+T cells, M1 type macrophages were increased in Lnc-PC overexpression tumors compared with the control group. Mechanism study showed that knocking down Lnc-PC reduced the stability of G3BP1 through ubiquitination degradation pathway, thus inhibiting the formation of G3BP1-induced liquid-liqudi phase separation (LLPS) and the recognition of dsRNA by RLRs. Furthermore, high level of Lnc-PC increased the PCa respond rate to ICB. CONCLUSIONS: Lnc-PC promoted the expression of ISGs, the chemotaxis of tumor supernatant to CD8+T cells and the response of tumor cells to IFN-γ, resulting in the increased expression of PD-L1 and MHC class I molecules on the surface of tumor cells. Mechanistically, Lnc-PC maintain the formation of G3BP1-induced LLPS by binding to G3BP1 and inhibiting its ubiquitination-mediated degradation. Thus, Lnc-PC activated RLRs signaling pathway and increased ISGs expression by promoting the recognition between RLRs and dsRNA. Lnc-PC also reprogramed the tumor microenvironment and induced anti-tumor immunity. Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e48 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Zean Li More articles by this author Huang Hai More articles by this author Luo Man-Li More articles by this author Expand All Advertisement PDF downloadLoading ...