LunX-CAR T Cells as a Targeted Therapy for Non-Small Cell Lung Cancer
LunX-CAR T Cells as a Targeted Therapy for Non-Small Cell Lung Cancer
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LunX-CAR T 细胞作为非小细胞肺癌的靶向治疗
DOI：
10.1016/j.omto.2020.04.008
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发表时间：
2020-06-26
影响因子：
5.7
通讯作者：
Wei, Haiming
中科院分区：
文献类型：
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作者：
Hu, Ziming;Zheng, Xiaohu;Wei, Haiming
非小细胞肺癌（NSCLC）具有很高的死亡率，并且缺乏有效的治疗。嵌合抗原受体（CAR）T细胞的治疗已被有效地用于血液恶性肿瘤，但对实体瘤的疗效并不令人满意。缺乏抗原靶标是这种有限功效的主要原因之一。以前，我们发现肺特异性X（LUNX;也称为BPIFA 1，PLC 1和SPLUNC 1）在肺癌细胞中过表达。在这里，我们构建了一种基于CAR-T细胞的策略来靶向LunX（CAR（LunX）T细胞）。CART细胞被开发为使得在特异性识别LunX后，它们分泌细胞因子并杀死LunX阳性NSCLC细胞。在体外，CAR（LunX）T细胞显示出对NSCLC细胞系和细胞因子产生的增强毒性，并显示出对NSCLC细胞的特异性LunX依赖性识别。CAR（LunX）T细胞的连续转移诱导了已建立的转移性肺癌异种移植物的消退并延长了存活。CAR（LunX）T细胞可以浸润到肿瘤中。此外，我们还构建了一个患者来源的肺癌异种移植模型。在用CAR（LunX）T细胞治疗后，肿瘤生长受到抑制，存活期显著延长。总之，我们的研究结果提供了LunX作为治疗NSCLC策略的免疫靶向的临床前证据。
Non-small cell lung cancer (NSCLC) carries a high mortality, and efficacious therapy is lacking. Therapy using chimeric antigen receptor (CAR) T cells has been used efficaciously against hematologic malignancies, but the curative effect against solid tumors is not satisfactory. A lack of antigen targets is one of the main reasons for this limited efficacy. Previously, we showed that lung-specific X (LUNX; also known as BPIFA1, PLUNC, and SPLUNC1) is overexpressed in lung cancer cells. Here, we constructed a CAR-T-cell-based strategy to target LunX (CAR(LunX) T cells). CART cells were developed so that, upon specific recognition of LunX, they secreted cytokines and killed LunX-positive NSCLC cells. In vitro, CAR(LunX) T cells displayed enhanced toxicity toward NSCLC lines and production of cytokines and showed specific LunX-dependent recognition of NSCLC cells. Adoptive transfer of CAR(LunX )T cells induced regression of established metastatic lung cancer xenografts and prolonged survival. CAR(LunX) T cells could infiltrate into the tumor. Also, we constructed a patient-derived xenograft model of lung cancer. After therapy with CAR(LunX) T cells, tumor growth was suppressed, and survival was prolonged significantly. Together, our findings offer preclinical evidence of the immunotherapeutic targeting of LunX as a strategy to treat NSCLC.