Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56
Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56
复制标题
工程化三重抑制受体抗性通过 CD56 提高抗肿瘤 CAR-T 细胞性能
DOI：
10.1038/s41467-019-11893-4
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发表时间：
2019-09-11
影响因子：
16.6
通讯作者：
Zhang, Hui
中科院分区：
文献类型：
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作者：
Zou, Fan;Lu, Lijuan;Zhang, Hui
抑制受体PD-1、Tim-3和Lag-3在肿瘤浸润淋巴细胞上高表达，影响其抗肿瘤活性。为了有效的癌症免疫治疗，重要的是防止嵌合抗原受体T （CAR-T）细胞衰竭。在这里，我们同时下调CAR-T细胞上的这三种检查点受体，并表明由此产生的PTL-CAR-T细胞经历表观遗传修饰并更好地控制肿瘤生长。此外，我们意外地发现PTL-CAR-T细胞的肿瘤浸润增加，并且它们在活的和坏死的肿瘤组织之间聚集。从机制上讲，PTL-CAR-T细胞上调CD56 (NCAM)，这对它们的效应功能至关重要。细胞间CD56分子之间的亲同相互作用与CAR-T细胞浸润增强、干扰素γ分泌增加以及CAR-T细胞存活时间延长有关。异位表达的CD56促进CAR-T细胞存活和抗肿瘤反应。我们的研究结果表明，三种检查点抑制受体的遗传阻断以及由此导致的CD56在CAR-T细胞上的高表达增强了对肿瘤生长的抑制。
The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-γ, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.