The N.1 Institute for Health, National University of Singapore, Singapore.
Department of Biomedical Engineering, National University of Singapore, Singapore.
Biomaterials. 2024 Mar;305:122460. doi: 10.1016/j.biomaterials.2023.122460. Epub 2024 Jan 2.
Ex vivo patient-derived tumor slices (PDTS) are currently limited by short-term viability in culture. Here, we show how bioengineered hydrogels enable the identification of key matrix parameters that significantly enhance PDTS viability compared to conventional culture systems. As demonstrated using single-cell RNA sequencing and high-dimensional flow cytometry, hydrogel-embedded PDTS tightly preserved cancer, cancer-associated fibroblast, and various immune cell populations and subpopulations in the corresponding original tumor. Cell-cell communication networks within the tumor microenvironment, including immune checkpoint ligand-receptor interactions, were also maintained. Remarkably, our results from a co-clinical trial suggest hydrogel-embedded PDTS may predict sensitivity to immune checkpoint inhibitors (ICIs) in head and neck cancer patients. Further, we show how these longer term-cultured tumor explants uniquely enable the sampling and detection of temporal evolution in molecular readouts when treated with ICIs. By preserving the compositional heterogeneity and complexity of patient tumors, hydrogel-embedded PDTS provide a valuable tool to facilitate experiments targeting the tumor microenvironment.
离体患者来源肿瘤切片（PDTS）目前在培养中受到短期存活率的限制。在这里，我们展示了生物工程水凝胶如何确定关键的基质参数，与传统培养系统相比，这些参数可显著提高 PDTS 的存活率。如单细胞 RNA 测序和高维流式细胞术所示，水凝胶包埋的 PDTS 紧密保留了癌症、癌症相关成纤维细胞和各种免疫细胞群体及其亚群在相应原始肿瘤中的状态。肿瘤微环境中的细胞间通讯网络，包括免疫检查点配体-受体相互作用，也得到了维持。值得注意的是，我们在一项合作临床试验中的结果表明，水凝胶包埋的 PDTS 可能预测头颈部癌症患者对免疫检查点抑制剂（ICI）的敏感性。此外，我们还展示了这些经过长期培养的肿瘤外植体如何独特地能够在接受 ICI 治疗时对分子读数的时间演变进行采样和检测。通过保留患者肿瘤的组成异质性和复杂性，水凝胶包埋的 PDTS 为针对肿瘤微环境的实验提供了有价值的工具。
