非小細胞腎細胞がんの免疫冷凍表現型と免疫チェックポイント阻害剤への反応への影響

Data regarding the clinical outcomes of immune checkpoint inhibitor (ICI) therapy and tumor immune microenvironment (TIME) profiles in non-clear-cell renal cell carcinoma (nccRCC) remain limited. Herein, we retrospectively compared the effectiveness profile of first-line ICI combination therapy between clear-cell RCC (ccRCC) and nccRCC. Additionally, genome-wide gene expression and tumor-infiltrating immune cell (TIIC) profiling were performed using RNA-seq and flow cytometry, respectively. Of 266 patients, 56 (21%) were histopathologically diagnosed with nccRCC. Progression-free survival (PFS) (hazard ratio [HR], 0.59, p = 0.0059) and overall survival (OS) (HR, 0.42, p = 0.0006) were shorter in nccRCC patients than in ccRCC patients. Gene expression analysis of 140 RCC samples revealed the downregulation of immune-related and angiogenesis-related pathways in nccRCC. The survival difference between ccRCC and nccRCC was more significant with the combination of ICIs and VEGFR-TKIs (PFS: HR 0.45, p = 0.0026; OS: HR 0.26, p <0.0001) than with dual ICI combinations (PFS: HR 0.64, p = 0.0761; OS: HR 0.59, p = 0.131). TIIC profiling of 116 samples showed that nccRCC exhibited an "immune-cold" TIME phenotype characterized by a decrease in TIICs, including CD8+ T cells. In conclusion, the downregulation of immune-related pathways, caused by an "immune-cold" TIME phenotype, is potentially involved in the pathogenesis underlying the decrease in the therapeutic efficacy of ICI combination therapy for nccRCC. Implications: nccRCC harbors an "immune-cold" TIME phenotype characterized by reduced TIICs, which in turn drive the downregulation of immune-related pathways and may contribute to decreased responsiveness to ICI therapy.