Leveraging patient-derived renal cell carcinoma organoids to enrich tumor-reactive t cells and identify novel immune checkpoints

You have accessJournal of UrologyCME1 Apr 2023MP04-18 LEVERAGING PATIENT-DERIVED RENAL CELL CARCINOMA ORGANOIDS TO ENRICH TUMOR-REACTIVE T CELLS AND IDENTIFY NOVEL IMMUNE CHECKPOINTS Elliot Merritt, Julie-Ann Cavallo, John Sfakianos, Amir Horowitz, Laura Zuluaga, Jordan Rich, Indu Saini, Kennedy E. Okhawere, Burak Upcinar, Ketan Badani, Benjamin Hopkins, and Anna Tocheva Elliot MerrittElliot Merritt More articles by this author , Julie-Ann CavalloJulie-Ann Cavallo More articles by this author , John SfakianosJohn Sfakianos More articles by this author , Amir HorowitzAmir Horowitz More articles by this author , Laura ZuluagaLaura Zuluaga More articles by this author , Jordan RichJordan Rich More articles by this author , Indu SainiIndu Saini More articles by this author , Kennedy E. OkhawereKennedy E. Okhawere More articles by this author , Burak UpcinarBurak Upcinar More articles by this author , Ketan BadaniKetan Badani More articles by this author , Benjamin HopkinsBenjamin Hopkins More articles by this author , and Anna TochevaAnna Tocheva More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003215.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite that renal cell carcinomas (RCC) are heavily infiltrated by intratumoral T cells, >70% of RCC patients fail to respond to immune checkpoint inhibitors (ICIs) immunotherapy. Our knowledge of the cellular and molecular mechanism underlying ICI efficacy in RCC is limited. Tumor cell-intrinsic IFNg responsivity has vital yet opposing functions in ICI efficacy by inducing the expression of antigen presenting molecules and T cell recruiting chemokine ligands from tumor cells, while in parallel increasing the expression of therapeutically relevant immune checkpoint ligands (IC-L) such as PD-L1. Major obstacles to improving ICI efficacy in RCC are the lack of (1) knowledge as it pertains to tumor-intrinsic IFNg responsivity; and (2) human models that recapitulate tumor cell heterogeneity and ICI responses. METHODS: We leverage patient-derived organoids (PDO) to determine IFNg-responsivity by analyzing the expression of antigen presenting molecule and IC-Ls. For each PDO, we generated blood and tumor derived PDO-reactive T cell lines that were phenotyped to determine T cell subset composition and inhibitory receptor expression. We performed PDO/T cell co-culture assays (PDOTs) and measured intracellular cytokine production to determine the increase in anti-tumor T cell reactivity in response to PD1 ICI and in combination with PDO relevant IC-Ls. RESULTS: We identified patient-specific intratumoral heterogeneity in IFNg responsivity to reveal IFNg-dependent and independent IC-L expression and soluble mediator secretion. Paired PDO IC-L expression and TIL checkpoint receptor expression data were used to identify ICI strategies in patient-specific manner. PDOTs were used to identify patient-specific therapeutically relevant IC-Ls, which in combination with PD-1 ICI improved anti-tumor T cell responses in autologous PDOT co-cultures. Functional immunophenotyping showed that in addition to CD8 T cells, intratumoral double negative T cells play a key role in ICI responses in RCC. CONCLUSIONS: PDO model intra-tumoral and inter-patient heterogeneity in the tumor-immune phenome and IFNg responsivity. Our paired autologous PDOT biobank enables patient-specific identification of targetable immune checkpoints and PDOT co-cultures enable characterization of patient-specific anti-tumor response to rationally design ICI combination therapies that augment anti-tumor T cell responses in RCC. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e40 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Elliot Merritt More articles by this author Julie-Ann Cavallo More articles by this author John Sfakianos More articles by this author Amir Horowitz More articles by this author Laura Zuluaga More articles by this author Jordan Rich More articles by this author Indu Saini More articles by this author Kennedy E. Okhawere More articles by this author Burak Upcinar More articles by this author Ketan Badani More articles by this author Benjamin Hopkins More articles by this author Anna Tocheva More articles by this author Expand All Advertisement PDF downloadLoading ...