Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Commun. 2021 Feb 5;12(1):808. doi: 10.1038/s41467-021-21068-9.
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 tumors, 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 build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
肉瘤样和横纹肌样（S/R）肾细胞癌（RCC）是具有侵袭性的肿瘤，其分子特征和临床特征有限。新出现的证据表明，免疫检查点抑制剂（ICI）对这些肿瘤特别有效，尽管其性质的生物学基础在很大程度上尚不清楚。在这里，我们评估了多个 S/R RCC 的临床试验和真实世界队列，以描述它们的分子特征、临床结果和免疫特征。我们发现 S/R RCC 肿瘤具有独特的分子特征，这可能解释了它们的侵袭性行为，包括 BAP1 突变、CDKN2A 缺失和 MYC 转录程序的表达增加。我们表明，这些肿瘤对 ICI 高度敏感，并且表现出免疫激活的特征，表现为免疫激活、增加的细胞毒性免疫浸润、抗原呈递机制基因的上调和 PD-L1 表达。我们的发现建立在先前的工作基础上，并阐明了 S/R RCC 侵袭性和对 ICI 反应性的分子驱动因素。
