为肝细胞癌武装 GPC3 CAR T 细胞:多少才足够,下一步是什么?
Armouring GPC3 CAR T cells for hepatocellular carcinoma: how much is enough and what comes next?
英文原题:In vitro integration of a functional vasculature to model endothelial regulation of chemotherapy and T-cell immunotherapy in liver cancer.
复杂的肿瘤微环境(TME)对开发针对实体瘤的有效疗法提出了重大挑战,凸显了对能够更好地再现TME生物学的先进体外模型的需求。
复杂的肿瘤微环境(TME)对有效实体瘤疗法的开发构成了重大挑战,凸显了对能够更好地再现TME生物学的先进体外模型的需求。为解决这一问题,我们利用微流控平台开发了一种血管化人肝肿瘤模型,旨在测试药物疗法和细胞疗法。该模型模拟了关键的致瘤特征,如缺氧、细胞外基质(ECM)和可灌注血管网络。血管内给予Sorafenib证明其能够显著破坏血管结构,同时在两种不同的肝肿瘤细胞系HepG2和Hep3b中引发异质性反应。此外,经工程化T细胞治疗显示,肿瘤血管系统阻碍了T细胞向肿瘤核心的浸润,但保留了其细胞毒性能力,尽管耗竭水平有所降低。对血管化肿瘤样本的细胞因子分析和空间 profiling 鉴定出可能增强T细胞介导抗肿瘤反应的促炎因子。通过捕捉关键的TME特征,该微流控平台提供了一种强大的工具,能够对肿瘤-免疫和肿瘤-血管相互作用进行详细研究。其多功能性可作为临床前研究与临床测试之间的有前景的桥梁,为开发和优化实体瘤的个性化治疗策略提供机会。
The complex tumor microenvironment (TME) presents significant challenges to the development of effective therapies against solid tumors, highlighting the need for advanced in vitro models that better recapitulate TME biology. To address this, we developed a vascularized human liver tumor model using a microfluidic platform, designed to test both drug and cell-based therapies. This model mimics critical tumorigenic features such as hypoxia, extracellular matrix (ECM), and perfusable vascular networks. Intravascular administration of Sorafenib demonstrated its ability to disrupt vascular structures significantly, while eliciting heterogeneous responses in two distinct liver tumor cell lines, HepG2 and Hep3b. Furthermore, treatment with engineered T-cells revealed that the tumor vasculature impeded T-cell infiltration into the tumor core but preserved their cytotoxic capacity, albeit with reduced exhaustion levels. Cytokine analysis and spatial profiling of vascularized tumor samples identified proinflammatory factors that may enhance T-cell-mediated antitumor responses. By capturing key TME characteristics, this microfluidic platform provides a powerful tool enabling detailed investigation of tumor-immune and tumor-vascular interactions. Its versatility could serve as a promising bridge between preclinical studies and clinical testing, offering opportunities for developing and optimizing personalized therapeutic strategies for solid tumors.
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