Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.
Clin Cancer Res. 2024 Oct 1;30(19):4530-4541. doi: 10.1158/1078-0432.CCR-23-2976.
Sarcoma encompasses a diverse group of cancers that are typically resistant to current therapies, including immune checkpoint blockade (ICB), and underlying mechanisms are poorly understood. The contexture of sarcomas limits generation of high-quality data using cutting-edge molecular profiling methods, such as single-cell RNA-sequencing, thus hampering progress in understanding these understudied cancers.
Here, we demonstrate feasibility of producing multimodal single-cell genomics and whole-genome sequencing data from frozen tissues, profiling 75,716 cell transcriptomes of five undifferentiated pleomorphic sarcoma and three intimal sarcoma samples, including paired specimens from two patients treated with ICB.
We find that genomic diversity decreases in patients with response to ICB, and, in unbiased analyses, identify cancer cell programs associated with therapy resistance. Although interactions of tumor-infiltrating T lymphocytes within the tumor ecosystem increase in ICB responders, clonal expansion of CD8+ T cells alone was insufficient to predict drug responses.
This study provides a framework for studying rare tumors and identifies salient and treatment-associated cancer cell intrinsic and tumor microenvironmental features in sarcomas.
肉瘤是一组多样化的癌症，通常对当前的治疗方法（包括免疫检查点阻断[ICB]）具有耐药性，其潜在机制尚不清楚。肉瘤的结构限制了使用前沿的分子分析方法（如单细胞 RNA 测序）生成高质量数据，从而阻碍了对这些研究不足的癌症的理解进展。
在这里，我们展示了从冷冻组织中生成多模态单细胞基因组学和全基因组测序数据的可行性，对五个未分化多形性肉瘤和三个内膜肉瘤样本的 75716 个细胞转录组进行了分析，包括两名接受 ICB 治疗的患者的配对标本。
我们发现对 ICB 有反应的患者的基因组多样性降低，并且在无偏分析中，确定了与治疗耐药性相关的癌症细胞程序。尽管肿瘤生态系统中肿瘤浸润 T 淋巴细胞的相互作用在 ICB 应答者中增加，但 CD8+T 细胞的克隆扩增本身不足以预测药物反应。
本研究为研究罕见肿瘤提供了一个框架，并确定了肉瘤中显著且与治疗相关的肿瘤细胞内在和肿瘤微环境特征。
