Regulatory T Cell Gene Signatures In Sarcomatoid Renal Cell Carcinoma

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP39)1 Sep 2021MP39-16 REGULATORY T CELL GENE SIGNATURES IN SARCOMATOID RENAL CELL CARCINOMA Phillip M Rappold, Fengshen Kuo, Paul Russo, Jonathan Coleman, Martin H Voss, Timothy A Chan, Ed Reznik, Robert J Motzer, Satish K Tickoo, and A Ari Hakimi Phillip M RappoldPhillip M Rappold More articles by this author , Fengshen KuoFengshen Kuo More articles by this author , Paul RussoPaul Russo More articles by this author , Jonathan ColemanJonathan Coleman More articles by this author , Martin H VossMartin H Voss More articles by this author , Timothy A ChanTimothy A Chan More articles by this author , Ed ReznikEd Reznik More articles by this author , Robert J MotzerRobert J Motzer More articles by this author , Satish K TickooSatish K Tickoo More articles by this author , and A Ari HakimiA Ari Hakimi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002054.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recent molecular characterization of the aggressive sarcomatoid renal cell carcinoma (sRCC) has revealed a highly inflamed tumor microenvironment (TME) and emerging clinical data suggest these tumors are highly responsive to immune checkpoint inhibition. Regulatory T cells (Tregs) are known to infiltrate the TME and exert immunosuppressive effects. Accordingly, increased Treg infiltrates in clear cell RCC (ccRCC) have been associated with poor outcomes, yet their role in sRCC remains unclear. METHODS: Normalized gene-level RNA sequencing (RNAseq) data for the TCGA KIRC (n=383 ccRCC, n=31 sRCC), IMmotion150 trial (n=218 ccRCC, n=43 sRCC), and IMmotion151 trial (n=688 ccRCC, n=134 sRCC) cohorts were obtained, infiltration levels for immune cell types and angiogenesis scores were quantified using the ssGSEA. For Kaplan-Meier analysis, Treg scores were individually annotated above/below median values to categorize patients into 2 groups (Treghi vs Treglo), then overall survival (OS) was tested with log-rank testing. Fluorescence activated cell sorting (FACS) was performed on ccRCC tumor specimens to sort tumor infiltrating immune cell populations, which were then used to generate RNA-seq gene expression profiles of the sorted populations. RESULTS: Immune deconvolution of RNAseq data from the TCGA cohort revealed enrichment of CTLA-4, PD-1, and Treg gene signatures along with decreased angiogenesis gene signatures in sRCC compared to ccRCC tumors (Wilcoxon rank sum; p < 0.05). Similar gene expression profiles emerged from the IMmotion150 and IMmotion151 cohorts. RNAseq on FACS sorted cells from RCC tumors revealed Tregs as the predominant source of CTLA-4 transcripts. Kaplan-Meier analysis of sRCC tumors from the TCGA cohort revealed Treghi tumors were associated with decreased OS compared to Treglo tumors (p < 0.0001). CONCLUSIONS: Transcriptomic analysis of sRCC tumors reveals an overall immunosuppressive tumor microenvironment with a lower degree of angiogenesis than ccRCC. sRCC tumors exhibited higher expression of coinhibitory molecules including PD-1 and CTLA-4 and higher Treg infiltrates. Furthermore, higher Treg infiltrates were significantly associated with worse OS. The high Treg and CTLA-4 signatures may explain the high response rates to therapeutic regimens including anti-CTLA-4 antibodies in sRCC. Further study will be needed to confirm the higher Treg densities in situ and to test the ability of Treg-related gene signatures to predict response to anti-CTLA-4 therapy in patients with sRCC. Source of Funding: NIH/NCI Cancer Center Support Grant (CCSG, P30 CA008748); Weiss Family Fund © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e710-e711 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Phillip M Rappold More articles by this author Fengshen Kuo More articles by this author Paul Russo More articles by this author Jonathan Coleman More articles by this author Martin H Voss More articles by this author Timothy A Chan More articles by this author Ed Reznik More articles by this author Robert J Motzer More articles by this author Satish K Tickoo More articles by this author A Ari Hakimi More articles by this author Expand All Advertisement PDF downloadLoading ...