PD40-01 CHARACTERIZATION OF THE TUMOR IMMUNE MICROENVIRONMENT IN CLEAR CELL RENAL CELL CARCINOMA (ccRCC): PROGNOSTIC VALUE AND THERAPEUTIC IMPLICATIONS OF AN M0-MACROPHAGE ENRICHED SUBTYPE

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II (PD40)1 Sep 2021PD40-01 CHARACTERIZATION OF THE TUMOR IMMUNE MICROENVIRONMENT IN CLEAR CELL RENAL CELL CARCINOMA (ccRCC): PROGNOSTIC VALUE AND THERAPEUTIC IMPLICATIONS OF AN M0-MACROPHAGE ENRICHED SUBTYPE Mark Farha, Randy Vince, Srinivas Nallandhighal, Judith Stangl-Kremser, Steven Goldenthal, Daniel Triner, Todd Morgan, Ganesh Palapattu, Aaron Udager, and Simpa Salami Mark FarhaMark Farha More articles by this author , Randy VinceRandy Vince More articles by this author , Srinivas NallandhighalSrinivas Nallandhighal More articles by this author , Judith Stangl-KremserJudith Stangl-Kremser More articles by this author , Steven GoldenthalSteven Goldenthal More articles by this author , Daniel TrinerDaniel Triner More articles by this author , Todd MorganTodd Morgan More articles by this author , Ganesh PalapattuGanesh Palapattu More articles by this author , Aaron UdagerAaron Udager More articles by this author , and Simpa SalamiSimpa Salami More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002050.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The number of approved immune checkpoint blockade (ICB) agents for patients with clear cell renal cell carcinoma (ccRCC) is growing. Here, we characterized the tumor immune microenvironment (TIME) subtypes in ccRCC and evaluate their capacity to predict ICB response. METHODS: Whole transcriptome data from patients in The Cancer Genome Atlas KIRC (TCGA-KIRC) was utilized for discovery (n=537). CIBERSORT was used for immune cell deconvolution. Unsupervised hierarchical clustering divided the cohort based on similar immune profiles. Progression free survival (PFS) and overall survival (OS) of each cluster was analyzed, and Gene Set Enrichment analysis (GSEA) was performed. The tumor immune dysfunction and exclusion (TIDE) tool, which uses a genomic signature validated on immunotherapy treated melanoma to model tumor immune evasion, was used to predict response to ICB in the TCGA-KIRC clusters. A cohort of nivolumab-treated patients from the CheckMate (CM)-010 and -025 trials (n=133) was used for validation. RESULTS: In non-metastatic patients within the discovery cohort, we identified a distinct M0hi cluster which demonstrated decreased PFS (40.4 mo vs. NR, p<0.0001) and OS (45.3 mo vs. NR, p<0.0001). The M0hi cluster was characterized by lower PD-L1 expression (p = 0.0032), enrichment of epithelial to mesenchymal transition (EMT; p=0.001), and angiogenesis [p=0.002] hallmark genes. The M0hi cluster also showed higher T-Cell Exclusion (p= 1.5x10-12), predominance of Cancer Associated Fibroblasts (CAFs; p= 8.3x10-14) and Myeloid Derived Suppressor Cells (MDSCs; p=1.1x10-7). The M0hi cluster had the lowest predicted response to immunotherapy using the TIDE tool (6% vs. 26%). In CM-010 and CM-025 trials, patients in quintiles Q3-5 of M0-macrophage content demonstrated significantly decreased OS after nivolumab treatment (20.7 mo (95% CI: 14.4-28.2) vs 43.3 mo (95% CI:22.7 – inf). Further, subjects in the highest M0 quintile showed EMT and Angiogenesis gene enrichment in ssGSEA analysis compared to those in the lowest (p=0.032 and p=0.057, respectively). CONCLUSIONS: Here, we identified a distinct ccRCC cluster associated with aggressive behavior defined molecularly by decreased PD-L1, increased EMT gene expression, and cellularly by enrichment of M0 macrophages, CAFs, MDSCs, and T Cell exclusion. M0 enrichment was found to be associated with poor OS in nivolumab treated patients. These findings warrant prospective validation to facilitate patient selection for ICB. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e674-e674 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mark Farha More articles by this author Randy Vince More articles by this author Srinivas Nallandhighal More articles by this author Judith Stangl-Kremser More articles by this author Steven Goldenthal More articles by this author Daniel Triner More articles by this author Todd Morgan More articles by this author Ganesh Palapattu More articles by this author Aaron Udager More articles by this author Simpa Salami More articles by this author Expand All Advertisement PDF downloadLoading ...