부산대학교 도서관

Simple Summary: Until recently, checkpoint inhibitors have largely been reserved for the metastatic disease space in clear cell renal cell carcinoma (ccRCC). Over the last several years, a growing body of trials have investigated the application of checkpoint inhibitor therapy in the neoadjuvant and adjuvant settings. However, these trials have yielded mixed results, due largely in part to a lack of high-fidelity biomarkers for patient selection and response prediction. Here, we present a simple workflow leveraging genomic data to characterize the immune microenvironment in ccRCC and identify a key macrophage subset that is associated with aggressive tumor biology, poor prognosis, and decreased response to immune checkpoint blockade (ICB). This work lays the foundation for future mechanistic discovery and prospective validation of integrating macrophage content into a ccRCC immune checkpoint blockade biomarker strategy. There is a need to optimize the treatment of clear cell renal cell carcinoma (ccRCC) patients at high recurrence risk after nephrectomy. We sought to elucidate the tumor immune microenvironment (TIME) of localized ccRCC and understand the prognostic and predictive characteristics of certain features. The discovery cohort was clinically localized patients in the TCGA-Kidney Renal Clear Cell Carcinoma (KIRC) project (n = 382). We identified an M0 macrophage-enriched cluster (n = 25) in the TCGA-KIRC cohort. This cluster's median progression-free survival (PFS) and overall survival (OS) were 40.4 and 45.3 months, respectively, but this was not reached in the others (p = 0.0003 and <0.0001, respectively). Gene set enrichment (GSEA) analysis revealed an enrichment of epithelial to mesenchymal transition and cell cycle progression genes within this cluster, and these patients also had a lower predicted response to immune checkpoint blockade (ICB) (4% vs. 20–34%). An M0-enriched cluster (n = 9) with shorter PFS (p = 0.0006) was also identified in the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort (n = 94). Through this characterization of the TIME in ccRCC, a cluster of patients defined by enrichment in M0 macrophages was identified that demonstrated poor prognosis and lower predicted ICB response. Pending further validation, this signature can identify localized ccRCC patients at high risk of recurrence after nephrectomy and who may require therapeutic approaches beyond ICB monotherapy. [ABSTRACT FROM AUTHOR]