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肝脏髓性来源的抑制细胞对小鼠肝癌转移的影响和其对靶向CEA-CAR-T细胞抗肿瘤活性的...

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发表于 2016-1-10 09:45:40 | 显示全部楼层 |阅读模式
Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T .
Chimeric antigen receptor-modified T cell (CAR-T) technology, a promising immunotherapeutic tool, has not been applied specifically to treat liver metastases (LM). While CAR-T delivery to LM can be optimized by regional intrahepatic infusion, we propose that liver CD11b+Gr-1+ myeloid-derived suppressor cells (L-MDSC) will inhibit the efficacy of CAR-T in the intrahepatic space. We studied anti-CEA CAR-T in a murine model of CEA+ LM and identified mechanisms through which L-MDSC expand and inhibit CAR-T function. We established CEA+ LM in mice and studied purified L-MDSC and responses to treatment with intrahepatic anti-CEA CAR-T infusions. L-MDSC expanded threefold in response to LM, and their expansion was dependent on GM-CSF, which was produced by tumor cells. L-MDSC utilized PD-L1 to suppress anti-tumor responses through engagement of PD-1 on CAR-T. GM-CSF, in cooperation with STAT3, promoted L-MDSC PD-L1 expression. CAR-T efficacy was rescued when mice received CAR-T in combination with MDSC depletion, GM-CSF neutralization to prevent MDSC expansion, or PD-L1 blockade. As L-MDSC suppressed anti-CEA CAR-T, infusion of anti-CEA CAR-T in tandem with agents targeting L-MDSC is a rational strategy for future clinical trials.
肝脏髓性来源的抑制细胞对小鼠肝癌转移的影响和其对靶向CEA-CAR-T细胞抗肿瘤活性的抑制作用
CAR-T细胞治疗技术,一个很有前途的免疫治疗工具,还没有运用在肝癌转移的特异性治疗上。然而,CAR-T用于治疗肝癌转移能够通过局部肝内灌注得到优化。我们预计肝脏CD11b+Gr-1+髓性来源的抑制细胞(L-MDSC)将会对CAR-T细胞在肝脏空间内有抑制作用。我们构建一个CEA+的LM小鼠模型,并且通过L-MDSC的扩增和抑制CAR-T的功能来研究其作用的机制。我们建立了CEA+的LM小鼠模型,研究纯化的L-MDSC,以及对肝脏内注射靶向CEA CAR-T的反应。L-MDSC由于LM的存在扩增了三倍,它们的扩增依赖于肿瘤细胞产生的GM-CSF。L-MDSC利用PD-L1来抑制抗肿瘤活性。GM-CSF,和STAT3一起,促进了L-MDSC PD-L1的表达。CAR-T的作用会得到恢复,当MDSC耗尽的时候。GM-CSF中和来防止MDSC的扩增,或者是PD-1的阻断。因为L-MDSC有抑制靶向CEA CAR-T细胞的作用,在临床中CAR-T细胞联合靶向L-MDSC的药物是将来临床试验中的一个理性的策略。
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