Xu Yuexin, Miller Chris P, Xue Jun, Zheng Ying, Warren Edus H, Tykodi Scott S, Akilesh Shreeram
Fred Hutchinson Cancer Center.
University of Washington.
Res Sq. 2023 Nov 10:rs.3.rs-3558517. doi: 10.21203/rs.3.rs-3558517/v1.
Tumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma (ccRCC).
We purified tumor and matched normal endothelial cells (NECs) from ccRCC specimens and performed single-cell RNA-sequencing to create a reference-quality atlas available as a searchable web resource for gene expression patterns. We established paired primary TECs and NECs cultures for ex vivo functional testing.
TECs from multiple donors shared a common phenotype with increased expression of pathways related to extracellular matrix regulation, cell-cell communication, and insulin-like growth factor signaling that was conserved in comparison to hepatocellular carcinoma associated TECs, suggesting convergent TEC phenotypes between unrelated tumors. Cultured TECs stably maintained a core program of differentially regulated genes, were inherently resistant to apoptosis after vascular endothelial growth factor removal and displayed increased adhesiveness to subsets of immune cells including regulatory T-cells.
Our studies delineate unique functional and phenotypic properties of TECs, which may provide insights into their interactions with available and emerging therapies. Functional phenotypes of cultured TECs suggest potential mechanisms of resistance to both antiangiogenic and immune-based therapies.
肿瘤内皮细胞（TECs）是肿瘤微环境与循环免疫细胞之间的主要界面，然而在高血管化的透明细胞肾细胞癌（ccRCC）中，其表型尚未完全明确。
我们从ccRCC标本中纯化肿瘤内皮细胞和匹配的正常内皮细胞（NECs），并进行单细胞RNA测序，以创建一个具有参考质量的图谱，作为一个可搜索的网络资源用于基因表达模式研究。我们建立了配对的原代TECs和NECs培养物用于体外功能测试。
来自多个供体的TECs具有共同的表型，与细胞外基质调节、细胞间通讯和胰岛素样生长因子信号传导相关的通路表达增加，与肝细胞癌相关的TECs相比，该表型具有保守性，提示不相关肿瘤之间存在趋同的TEC表型。培养的TECs稳定维持差异调节基因的核心程序，在去除血管内皮生长因子后对凋亡具有固有抗性，并对包括调节性T细胞在内的免疫细胞亚群表现出增加的粘附性。
我们的研究描绘了TECs独特的功能和表型特性，这可能为深入了解它们与现有和新兴疗法的相互作用提供见解。培养的TECs的功能表型提示了对抗血管生成和免疫疗法耐药的潜在机制。
