Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors¹⁻³, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD−L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

中文翻译：

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肉瘤样和横纹肌样肾细​​胞癌的综合分子表征揭示了不良预后和对免疫检查点抑制剂反应的决定因素。

肉瘤样和横纹肌样（S / R）肾细胞癌（RCC）是高度侵袭性的肿瘤，其分子和临床特征有限。新兴证据表明免疫检查点抑制剂（ICI）对于这些肿瘤^1-3特别有效，尽管该属性的生物学基础在很大程度上尚不清楚。在这里，我们评估了S / R RCC的多个临床试验和现实世界队列，以表征其分子特征，临床结果和免疫学特征。我们发现S / R RCC肿瘤具有独特的分子特征，可能解释了它们的攻击行为，包括BAP1突变，CDKN2A缺失和MYC转录程序表达增加。我们显示这些肿瘤对ICI高度敏感，并且表现出以免疫激活，细胞毒性免疫浸润增加，抗原呈递机制基因上调和PD-L1表达为特征的免疫炎症表型。我们的发现揭示了对S / R RCC肿瘤免疫检查点抑制剂的侵略性和反应性的分子驱动因素。