4572 Background: Metastatic clear cell renal cell carcinoma (ccRCC) has a 5-year survival of 12%, but the number of approved immune checkpoint blockade (ICB) agents is growing, necessitating the need to better identify responders. The composition and role of the tumor immune microenvironment (TIME) has yet to be comprehensively characterized in ccRCC. Here, we leveraged a genomic data driven approach to characterize TIME subtypes in ccRCC. Methods: Whole transcriptome data from patients with local and metastatic disease in the Cancer Genome Atlas KIRC (TCGA-KIRC) project was utilized (n = 537). CIBERSORT was used for immune cell deconvolution, and unsupervised hierarchical clustering divided the cohort based on similar immune profiles. Progression free (PFS) and overall (OS) survival of each cluster was analyzed, and Gene Set Enrichment analysis was performed among clusters. The tumor immune dysfunction and exclusion (TIDE) tool, which uses a genomic signature validated on immunotherapy treated melanoma patients to model tumor immune evasion, was then used to predict response to ICB in the TCGA-KIRC clusters. Results: There was a distinct M0hi cluster identified which demonstrated a higher proportion of patients with stage III/IV disease, decreased PFS and OS (Table). Additionally, the M0hi cluster was characterized by lower PD-L1 expression (ANOVA, p = 0.0045) and an enrichment of epithelial to mesenchymal transition (EMT) hallmark genes [Enrichment Score = 0.64, p = 0.001]. The M0hi cluster also showed a higher degree of T-Cell Exclusion (ANOVA, p = 2.2x10-16), predominance of Cancer Associated Fibroblasts (CAFs; ANOVA, p = 2.2x10-16) and Myeloid Derived Suppressor Cells (MDSCs; ANOVA, p = 4.1x10-10). The M0hi cluster had the lowest predicted response to immunotherapy using the TIDE tool (Table). Conclusions: Comprehensive characterization of the TCGA-KIRC cohort led to identification of a distinct cluster of ccRCC defined molecularly by decreased PD-L1 and increased EMT gene expression and cellularly by enrichment of M0 macrophages, CAFs, MDSCs, and an exclusion of T Cells. Patients within this cluster exhibited aggressive disease and poor predicted response to ICB. These findings warrant further validation to identify appropriate therapeutic approaches for this ccRCC subgroup.[Table: see text]
Prognostic Values of TIGAR Expression and 18F-FDG PET/CT in Clear Cell Renal Cell Carcinoma