Organoid Modeling of the Tumor Immune Microenvironment
Organoid Modeling of the Tumor Immune Microenvironment
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DOI：
10.1016/j.cell.2018.11.021
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发表时间：
2018-12-13
期刊：
影响因子：
64.5
通讯作者：
Kuo, Calvin J.
中科院分区：
文献类型：
--
作者：
Neal, James T.;Li, Xingnan;Kuo, Calvin J.
体外癌症培养物，包括三维类器官，通常只含有肿瘤上皮，但需要人工重建以重现肿瘤微环境（TME）。原发性肿瘤上皮细胞与内源性同源肿瘤浸润淋巴细胞（TIL）作为一个内聚单位的共培养一直特别难以捉摸。在此，空气-液体界面（ALI）方法将来自>100个人活检组织或小鼠肿瘤的患者来源的类器官（PDO）作为具有天然包埋免疫细胞（T、B、NK、巨噬细胞）的肿瘤上皮细胞在同源免疫活性宿主中增殖。稳健的基于液滴的单细胞同时测定基因表达和免疫库表明PDOTILs准确地保留了原始肿瘤T细胞受体（TCR）谱。至关重要的是，人和鼠PDO成功地模拟了免疫检查点阻断（ICB），其中抗PD-1和/或抗PD-L1扩增和激活肿瘤抗原特异性TIL并引发肿瘤细胞毒性。原发性肿瘤上皮细胞与内源性免疫基质的整体基于类器官的增殖应该能够在TME内进行免疫肿瘤学研究，并促进个性化免疫治疗测试。
In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDOTILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.