肿瘤细胞治疗研究
英文原题：Production of an interleukin-10 blocking antibody by genetically engineered macrophages increases cancer cell death in human gastrointestinal tumor slice cultures.
Production of an interleukin-10 blocking antibody by genetically engineered macrophages increases cancer cell death in human gastrointestinal tumor slice cultures.
尽管IL-10能够促进效应T细胞功能，但其在肿瘤微环境中的总体效应似乎是抑制性的；因此，阻断这一关键调节性细胞因子具有增强抗肿瘤免疫功能的治疗潜力。
尽管IL-10能够促进效应T细胞功能，但其在肿瘤微环境中的总体效应似乎具有抑制作用；因此，阻断这一关键调控细胞因子具有增强抗肿瘤免疫功能的治疗潜力。由于巨噬细胞能够高效地定位于TME，我们假设它们可以作为递送载体，用于递送旨在阻断该通路的药物。为验证我们的假设，我们构建并评估了能够产生IL-10阻断抗体（αIL-10）的基因工程巨噬细胞。健康供体人外周血单个核细胞经分化后，用编码BT-063（一种人源化αIL-10抗体）的新型慢病毒转导。αIL-10 GEMs的疗效在由胰腺导管腺癌原发肿瘤和结直肠癌肝转移切除标本建立的人胃肠道肿瘤切片培养模型中进行评估。LV转导使αIL-10 GEMs持续产生BT-063至少21天。流式细胞术评估显示，转导未改变GEM表型，但αIL-10 GEMs在TME中产生了可测量量的BT-063，这与肿瘤细胞凋亡率较对照组高约5倍相关。
Although it can promote effector T-cell function, the summative effect of interleukin-10 (IL-10) in the tumor microenvironment (TME) appears to be suppressive; therefore, blocking this critical regulatory cytokine has therapeutic potential to enhance antitumor immune function. As macrophages efficiently localize to the TME, we hypothesized that they could be used as a delivery vehicle for drugs designed to block this pathway. To test our hypothesis, we created and evaluated genetically engineered macrophages (GEMs) that produce an IL-10-blocking antibody (αIL-10). Healthy donor human peripheral blood mononuclear cells were differentiated and transduced with a novel lentivirus (LV) encoding BT-063, a humanized αIL-10 antibody. The efficacy of αIL-10 GEMs was assessed in human gastrointestinal tumor slice culture models developed from resected specimens of pancreatic ductal adenocarcinoma primary tumors and colorectal cancer liver metastases. LV transduction led to sustained production of BT-063 by αIL-10 GEMs for at least 21 days. Transduction did not alter GEM phenotype as evaluated by flow cytometry, but αIL-10 GEMs produced measurable quantities of BT-063 in the TME that was associated with an ~5-fold higher rate of tumor cell apoptosis than control.
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