Bispecific CD3-HAC carried by E1A-engineered mesenchymal stromal cells against metastatic breast cancer by blocking PD-L1 and activating T cells
Bispecific CD3-HAC carried by E1A-engineered mesenchymal stromal cells against metastatic breast cancer by blocking PD-L1 and activating T cells
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E1A工程间充质基质细胞携带双特异性CD3-HAC，通过阻断PD-L1和激活T细胞来对抗转移性乳腺癌
DOI：
10.1186/s13045-019-0723-8
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发表时间：
2019
影响因子：
28.5
通讯作者：
Xiong Dongsheng
中科院分区：
文献类型：
--
作者：
Yang Yuanyuan;Zhang Xiaolong;Lin Fangzhen;Xiong Mengshang;Fan Dongmei;Yuan Xiangfei;Lu Yang;Song Yuewen;Zhang Yizi;Hao Mu;Ye Zhou;Zhang Yanjun;Wang Jianxiang;Xiong Dongsheng
背景PD-1/PD-L1阻断剂在转移性癌症的治疗中可以提供持久的益处，但其反应率仍然适中，并且有时会发生潜在的不良反应。将免疫抑制剂集中在疾病部位被认为可以打破局部免疫耐受并减少全身毒性。E1A工程化间充质基质细胞（MSC. E1A）是一种具有导向和治疗肿瘤转移的转移系统，通过局部复制的腺病毒修饰肿瘤细胞，使其释放抗CD3单链抗体与高亲和力共有（HAC）PD-1连接的双功能融合蛋白CD3-HAC。方法将人端粒酶逆转录酶（human telomerase reverse transcriptase，hTERT）启动子驱动的CD3-HAC基因构建成腺病毒载体，将E1A基因构建成慢病毒载体。以萤火虫荧光素酶标记的MSC（MSC. Luc）为材料，通过生物发光成像（BLI）分析MSC在体内的归巢特性。CD3-HAC诱导的T细胞对PD-L1阳性细胞的细胞毒性在体外和体内检测与5-FU. ResultsOur数据表明，CD3-HAC可以特异性结合PD-L1阳性肿瘤细胞，并诱导淋巴细胞介导的溶解有效地在体外和体内。HAC的干预降低了PD-1/PD-L1轴对暴露于MDA-MB-231细胞的T细胞的作用，并增加了淋巴细胞活化。AdCD3-HAC联合LentiR. E1A感染的MSCs可特异性迁移至乳腺癌转移灶，并在肿瘤部位产生腺病毒。此外，治疗与MSC.CD3-HAC.E1A与5-FU的组合显着抑制肿瘤的生长在mice. ConclusionsThis腺病毒加载MSC.E1A系统提供了一个有前途的战略，为识别和消除转移与局部释放的免疫调节剂。
BackgroundPD-1/PD-L1 blockade can confer durable benefits in the treatment of metastatic cancers, but the response rate remains modest and potential adverse effects occur sometimes. Concentrating immunotherapeutic agents at the site of disease was believed to break local immune tolerance and reduce systemic toxicity. E1A-engineered mesenchymal stromal cell (MSC.E1A) was an attractive transfer system that preferentially homing and treating cancer metastasis, through which the tumor cells were modified by locally replicated adenoviruses to release CD3-HAC, a bifunctional fusion protein that anti-CD3 scfv linked with high-affinity consensus (HAC) PD-1. Subsequently, CD3-HAC, wbich was bound on PD-L1-positive breast cancer cells, recruited T cells to exhibit a potent antitumor immunity incombination with immune checkpoint blockade.MethodsWe constructed the CD3-HAC gene driven by human telomerase reverse transcriptase (hTERT) promoter into an adenoviral vector and the E1A gene into the lentiviral vector. The homing property of MSCs in vivo was analyzed with firefly luciferase-labeled MSCs (MSC.Luc) by bioluminescent imaging (BLI). The cytotoxicity of T cells induced by CD3-HAC towards PD-L1-positive cells was detected in vitro and in vivo in combination with 5-FU.ResultsOur data suggest that CD3-HAC could specifically bind to PD-L1-positive tumor cells and induce lymphocyte-mediated lysis effectively both in vitro and in vivo. The intervention with HAC diminished the effects of PD-1/PD-L1 axis on T cells exposed to MDA-MB-231 cells and increased lymphocytes activation. MSCs infected by AdCD3-HAC followed by LentiR.E1A could specially migrate to metastasis of breast cancer and produce adenoviruses in the tumor sites. Furthermore, treatment with MSC.CD3-HAC.E1A in combination with 5-FU significantly inhibited the tumor growth in mice.ConclusionsThis adenovirus-loaded MSC.E1A system provides a promising strategy for the identification and elimination of metastasis with locally released immuno-modulator.