BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Front Immunol. 2018 Mar 6;9:416. doi: 10.3389/fimmu.2018.00416. eCollection 2018.
In the hepatitis B virus (HBV)-related hepatocellular carcinoma tumor microenvironment (TME), monocytes reportedly impede natural T cell functions PD-L1/PD-1 signaling. However, it remains unclear if T cell receptor-redirected T cells (TCR T cells) are similarly inhibited. Hence, we developed a 3D intrahepatic TME microfluidic model to investigate the immunosuppressive potential of monocytes toward HBV-specific TCR T cells and the role of PD-L1/PD-1 signaling. Interestingly, in our 3D static microfluidic model, we observed that monocytes suppressed only retrovirally transduced (Tdx) TCR T cell cytotoxicity toward cancer cells PD-L1/PD-1, while mRNA electroporated (EP) TCR T cell cytotoxicity was not affected by the presence of monocytes. Importantly, when co-cultured in 2D, both Tdx and EP TCR T cell cytotoxicity toward cancer cells were not suppressed by monocytes, suggesting our 3D model as a superior tool compared to standard 2D assays for predicting TCR T cell efficacy in a preclinical setting, which can thus be used to improve current immunotherapy strategies.
在乙型肝炎病毒（HBV）相关的肝细胞癌肿瘤微环境（TME）中，据报道单核细胞会抑制自然 T 细胞的功能，PD-L1/PD-1 信号通路。然而，目前尚不清楚 T 细胞受体重定向的 T 细胞（TCR T 细胞）是否也受到抑制。因此，我们开发了一种 3D 肝内 TME 微流控模型，以研究单核细胞对 HBV 特异性 TCR T 细胞的免疫抑制潜力以及 PD-L1/PD-1 信号通路的作用。有趣的是，在我们的 3D 静态微流控模型中，我们观察到单核细胞仅抑制逆转录病毒转导（Tdx）TCR T 细胞对癌细胞的细胞毒性作用和 PD-L1/PD-1，而单核细胞的存在并不影响 mRNA 电穿孔（EP）TCR T 细胞的细胞毒性。重要的是，当在 2D 中共培养时，单核细胞不会抑制 Tdx 和 EP TCR T 细胞对癌细胞的细胞毒性，这表明我们的 3D 模型是一种优于标准 2D 测定的工具，可用于预测临床前环境中 TCR T 细胞的功效，从而可以改进当前的免疫治疗策略。
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