{"title":"Non-Clear Cell Renal Cell Carcinoma Has an Immune-Cold Phenotype That Affects Response to Immune Checkpoint Inhibitors.","authors":"Hiroki Ishihara, Yu-Yu Liu, Riu Yamashita, Hironori Fukuda, Yukihiro Mizoguchi, Makiko Yamashita, Shigehisa Kitano, Kazunori Aoki, Hidekazu Tachibana, Shinsuke Mizoguchi, Koichi Nishimura, Takayuki Nakayama, Yuki Nemoto, Kazuhiko Yoshida, Toshihito Hirai, Junpei Iizuka, Yoji Nagashima, Toshikazu Ushijima, Daisuke Tokita, Tsunenori Kondo, Toshio Takagi","doi":"10.1158/1541-7786.MCR-25-0939","DOIUrl":null,"url":null,"abstract":"<p><p>Data on 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. In this study, we retrospectively compared the effectiveness profile of first-line ICI combination therapy between clear-cell renal cell carcinoma (ccRCC) and nccRCC. Additionally, genome-wide gene expression and tumor-infiltrating immune cell (TIIC) profiling were performed using RNA sequencing 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 patients with nccRCC than in patients with ccRCC. 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 vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI; 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.</p><p><strong>Implications: </strong>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.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"390-400"},"PeriodicalIF":4.7000,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1541-7786.MCR-25-0939","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Data on 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. In this study, we retrospectively compared the effectiveness profile of first-line ICI combination therapy between clear-cell renal cell carcinoma (ccRCC) and nccRCC. Additionally, genome-wide gene expression and tumor-infiltrating immune cell (TIIC) profiling were performed using RNA sequencing 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 patients with nccRCC than in patients with ccRCC. 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 vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI; 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.
期刊介绍：
Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.
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