MP14-14 HNRNPL INDUCED CIRCFAM13B INCREASED BLADDER CANCER IMMUNOTHERAPY SENSITIVITY VIA INHIBITING GLYCOLYSIS THROUGH IGF2BP1/PKM2 PATHWAY

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP14-14 HNRNPL INDUCED CIRCFAM13B INCREASED BLADDER CANCER IMMUNOTHERAPY SENSITIVITY VIA INHIBITING GLYCOLYSIS THROUGH IGF2BP1/PKM2 PATHWAY Qiang Lv, Xiao Yang, Qiang Cao, and Jiancheng Lv Qiang LvQiang Lv More articles by this author , Xiao YangXiao Yang More articles by this author , Qiang CaoQiang Cao More articles by this author , and Jiancheng LvJiancheng Lv More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003234.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The response rate to immunotherapy in patients with bladder cancer (BCa) remains relatively low. Considering the stable existence and important functions in tumour metabolism, the role of circRNAs in regulating immune escape and immunotherapy sensitivity is receiving increasing attention. METHODS: Circular RNA (circRNA) sequencing was performed on five pairs of BCa samples, and circFAM13B was screened out because of its remarkably low expression in BCa. Further mRNA sequencing was conducted, and the association of circFAM13B with glycolysis process and CD8+ T cell activation was confirmed. The functions of circFAM13B were verified by proliferation assays, glycolysis assays, BCa cells-CD8+ T cell co-culture assays and tumorigenesis experiment among human immune reconstitution NOG mice. Bioinformatic analysis, RNA-protein pull down, mass spectrometry, RNA immunoprecipitation, luciferase reporter assay and fluorescence in situ hybridization were performed to validate the HNRNPL/circFAM13B/IGF2BP1/PKM2 cascade. RESULTS: Low expression of circFAM13B was observed in BCa, and it was positively associated with lower tumour stage and better prognosis among patients with BCa. The function of CD8+ T cells was promoted by circFAM13B, and it could attenuate the glycolysis of BCa cells and reverse the acidic tumour microenvironment (TME). The production of granzyme B and IFN-γ was improved, and the immunotherapy (PD-1 antibodies) sensitivity was facilitated by the inhibition of acidic TME. Mechanistically, circFAM13B was competitively bound to the KH3-4 domains of IGF2BP1 and subsequently reduced the binding of IGF2BP1 and PKM2 3’UTR. Thus, the stability of the PKM2 mRNA decreased, and glycolysis-induced acidic TME was inhibited. The generation of circFAM13B was explored by confirming whether HNRNPL could promote circFAM13B formation via pre-mRNA back-splicing. CONCLUSIONS: HNRNPL-induced circFAM13B could repress immune evasion and enhance immunotherapy sensitivity by inhibiting glycolysis and acidic TME in BCa through the novel circFAM13B/IGF2BP1/PKM2 cascade. Therefore, circFAM13B can be used as a biomarker for guiding the immunotherapy among patients with BCa. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e188 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Qiang Lv More articles by this author Xiao Yang More articles by this author Qiang Cao More articles by this author Jiancheng Lv More articles by this author Expand All Advertisement PDF downloadLoading ...