Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics, Boston, MA 02115, USA.
Cancer Cell. 2021 May 10;39(5):649-661.e5. doi: 10.1016/j.ccell.2021.02.015. Epub 2021 Mar 11.
Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.
免疫检查点阻断（ICB）可使一部分晚期肾细胞癌（RCC）患者获得持久的疾病控制，但耐药机制仍不清楚。我们对接受 ICB 治疗前后的转移性 RCC 患者的肿瘤和免疫细胞的单细胞转录组进行了分析。在应答者中，细胞毒性 T 细胞的亚群表达更高水平的共抑制受体和效应分子。治疗活检中的巨噬细胞在富含干扰素的微环境中向促炎状态转变，但也上调了免疫抑制标志物。在癌细胞中，我们发现，在 ICB 治疗后，细胞分裂成两个亚群，在血管生成信号和免疫抑制程序的上调方面存在差异。在原发性和 ICB 治疗的晚期 RCC 中，癌细胞亚群和免疫逃避的表达特征与 PBRM1 突变和生存相关。我们的研究结果表明，ICB 重塑了 RCC 微环境，并改变了肿瘤细胞和免疫细胞之间相互作用的关键因素，这些因素对于理解 ICB 的反应和耐药性至关重要。
Zotero 插件
