Non–Clear Cell Renal Cell Carcinoma Has an Immune-Cold Phenotype That Affects Response to Immune Checkpoint Inhibitors

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.