通过rediocide-A 靶向 CD155 克服了自然杀伤细胞对肿瘤的免疫抵抗。
Targeting CD155 by rediocide-A overcomes tumour immuno-resistance to natural killer cells.
机构信息
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
出版信息
Pharm Biol. 2021 Dec;59(1):47-53. doi: 10.1080/13880209.2020.1865410.
CONTEXT
Therapeutic benefits of immunotherapy are restricted by cancer immune-resistance mechanisms. Rediocide-A (Red-A), a natural product extracted from Traditional Chinese Medicine, is a promising agent to battle against cancer which acts as an immune checkpoint inhibitor.
OBJECTIVE
To investigate the effect of Red-A on NK-cell tumouricidal activity.
MATERIALS AND METHODS
NK cells were co-cultured with A549 or H1299 cells and treated with 10 or 100 nM Red-A for 24 h. Cells treated with 0.1% dimethyl sulphoxide (DMSO) was employed as vehicle control. NK cell-mediated cytotoxicity was detected by biophotonic cytotoxicity and impedance assay. Degranulation, granzyme B, NK cell-tumour cell conjugates and ligands profiling were detected by flow cytometry. Interferon-γ (IFN- γ) production was assessed by enzyme-linked immunosorbent assay (ELISA).
RESULTS
Red-A increased NK cell-mediated lysis of A549 cells by 3.58-fold (21.86% vs. 78.27%) and H1299 cells by 1.26-fold (59.18% vs. 74.78%), compared to vehicle control. Granzyme B level was increased by 48.01% (A549 cells) and 53.26% (H1299 cells) after 100 nM Red-A treatment. INF-γ level was increased by 3.23-fold (A549 cells) and 6.77-fold (H1299 cells) after 100 nM Red-A treatment. Red-A treatment down-regulated the expression level of CD155 by 14.41% and 11.66% in A549 cells and H1299 cells, respectively, leading to the blockade of tumour immuno-resistance to NK cells.
CONCLUSIONS
Red-A overcomes immuno-resistance of NSCLCs to NK cells by down-regulating CD155 expression, which shows the possibility of developing checkpoint inhibitors targeting TIGIT/CD155 signalling to overcome immuno-resistance of cancer cells.
背景
免疫疗法的治疗益处受到癌症免疫抵抗机制的限制。Rediocide-A（Red-A）是从中药中提取的一种天然产物，是一种有前途的抗癌药物，可作为免疫检查点抑制剂。
目的
研究 Red-A 对 NK 细胞肿瘤杀伤活性的影响。
材料和方法
将 NK 细胞与 A549 或 H1299 细胞共培养，并分别用 10 或 100 nM Red-A 处理 24 小时。用 0.1%二甲基亚砜（DMSO）处理的细胞作为载体对照。通过生物光子细胞毒性和阻抗测定法检测 NK 细胞介导的细胞毒性。通过流式细胞术检测脱颗粒、颗粒酶 B、NK 细胞-肿瘤细胞结合物和配体谱。通过酶联免疫吸附试验（ELISA）评估干扰素-γ（IFN-γ）的产生。
结果
与载体对照相比，Red-A 使 NK 细胞介导的 A549 细胞裂解增加了 3.58 倍（21.86% vs. 78.27%），使 H1299 细胞裂解增加了 1.26 倍（59.18% vs. 74.78%）。用 100 nM Red-A 处理后，颗粒酶 B 水平在 A549 细胞中增加了 48.01%，在 H1299 细胞中增加了 53.26%。用 100 nM Red-A 处理后，IFN-γ 水平在 A549 细胞中增加了 3.23 倍，在 H1299 细胞中增加了 6.77 倍。Red-A 处理使 A549 细胞和 H1299 细胞中 CD155 的表达水平分别下调 14.41%和 11.66%，从而阻断肿瘤对 NK 细胞的免疫抵抗。
结论
Red-A 通过下调 CD155 表达克服了 NSCLC 对 NK 细胞的免疫抵抗，这表明开发针对 TIGIT/CD155 信号通路的检查点抑制剂以克服癌细胞免疫抵抗具有可能性。
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