MP88-20 ESTABLISHMENT OF NOVEL MOUSE BLADDER CANCER CELL LINES MIMICKING INTRINSIC SUBTYPE OF HUMAN INVASIVE BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2017MP88-20 ESTABLISHMENT OF NOVEL MOUSE BLADDER CANCER CELL LINES MIMICKING INTRINSIC SUBTYPE OF HUMAN INVASIVE BLADDER CANCER RYOICHI SAITO, Christof Smith, Jordan Kardos, Lisa Bixby, Shengjie Chai, Jeffrey Damrauer, Takanobu Utsumi, Sara Wobker, Bhavani Krishnan, Osamu Ogawa, Benjamin Vincent, and William Kim RYOICHI SAITORYOICHI SAITO More articles by this author , Christof SmithChristof Smith More articles by this author , Jordan KardosJordan Kardos More articles by this author , Lisa BixbyLisa Bixby More articles by this author , Shengjie ChaiShengjie Chai More articles by this author , Jeffrey DamrauerJeffrey Damrauer More articles by this author , Takanobu UtsumiTakanobu Utsumi More articles by this author , Sara WobkerSara Wobker More articles by this author , Bhavani KrishnanBhavani Krishnan More articles by this author , Osamu OgawaOsamu Ogawa More articles by this author , Benjamin VincentBenjamin Vincent More articles by this author , and William KimWilliam Kim More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2745AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Immune checkpoint inhibitors (ICI), such as anti-PD1/PDL1 antibody, have been proved to be effective in advanced human bladder cancer. But we still don't know why some patients respond to ICI but others not. In order to answer the question, preclinical mouse models mimicking the genetics of human bladder cancer are essential. We established two unique classes of novel mouse bladder cancer cell lines and examined if the syngeneic cell line tumors are applicable to immunological study of human bladder cancer. METHODS We established BBN cell lines from N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced mouse bladder cancer model and UPPL cell lines from Upk3a-CreERT2;Tp53 f/f; Pten f/f; Luciferase mouse model. Whole transcriptome profiling was performed on 12 BBN and 8 UPPL primary tumors. Unsupervised clustering and supervised clustering using BASE47, gene sets for identifying basal and luminal subtype, were performed. We treated the subcutaneous allografts of the established cell lines by anti-mouse Pdl1 antibody (10mg/kg, intraperitoneal injection, weekly) and analyzed the background of responders and non-responders with flow cytometry and T/B cell receptor (TCR/BCR) amplicon sequencing of tumor infiltrating lymphocytes. RESULTS Finally 12 BBN cell lines and 8 UPPL cell lines were established. Unsupervised clustering of BBN and UPPL models demonstrated close clustering with human basal and luminal bladder cancers, respectively. More interestingly, BBN tumors had significant enrichment of immune related genes (Figure). We treated the allograft tumors of BBN963, BBN975 and UPPL1541 cell lines with anti-mouse Pdl1 antibody. Half of the BBN963-derived tumors responded to the treatment but BBN975 and UPPL1541-derived tumors not. Paradoxically BBN975 tumors, the non-responders, showed higher infiltration of CD3+ T cells. CONCLUSIONS We established mouse bladder cancer cell lines mimicking human basal and luminal bladder cancer. BBN963 could be used as mixed response model and BBN975 could be used as immune exhaustion model. We are now trying to elucidate the mechanism of differential response of the BBN and UPPL tumors to Pd1/Pdl1 blockade. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1182 Advertisement Copyright & Permissions© 2017MetricsAuthor Information RYOICHI SAITO More articles by this author Christof Smith More articles by this author Jordan Kardos More articles by this author Lisa Bixby More articles by this author Shengjie Chai More articles by this author Jeffrey Damrauer More articles by this author Takanobu Utsumi More articles by this author Sara Wobker More articles by this author Bhavani Krishnan More articles by this author Osamu Ogawa More articles by this author Benjamin Vincent More articles by this author William Kim More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...