PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells
PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells
复制标题
DOI：
10.1080/2162402x.2017.1284722
复制
发表时间：
2017-02
期刊：
影响因子：
7.2
通讯作者：
Xinru Wei;Y. Lai;Jin Li;L. Qin;Youdi Xu;R. Zhao;Baiheng Li;Simiao Lin;Suna Wang;Qiting Wu-Qi
中科院分区：
文献类型：
--
作者：
Xinru Wei;Y. Lai;Jin Li;L. Qin;Youdi Xu;R. Zhao;Baiheng Li;Simiao Lin;Suna Wang;Qiting Wu-Qi
摘要近年来，免疫疗法，如涉及嵌合抗原受体（CAR）T细胞的免疫疗法，已成为越来越有前途的非小细胞肺癌（NSCLC）治疗方法。在这项研究中，我们探索了前列腺干细胞抗原（PSCA）重定向的CAR T和粘蛋白1（MUC1）重定向的CAR T细胞在NSCLC肿瘤模型中的抗肿瘤潜力。首先，我们建立了人NSCLC的患者来源的异种移植（PDX）小鼠模型，该模型保持了原发性肿瘤的抗原谱。接下来，我们证明了PSCA和MUC1在NSCLC中的表达，随后在体外产生并确认靶向PSCA和MUC1的CAR T细胞针对NSCLC细胞系的特异性和功效。最后，我们证明了靶向PSCA的CAR T细胞可以有效地抑制PDX小鼠中的NSCLC肿瘤生长，并在与靶向MUC1的CAR T细胞组合时协同消除PSCA+MUC1+肿瘤。总之，我们的研究表明，PSCA和MUC1都是NSCLC中有希望的CAR T细胞靶标，并且这些抗原的组合靶向可以进一步增强CAR T细胞的抗肿瘤功效。
ABSTRACT In recent years, immunotherapies, such as those involving chimeric antigen receptor (CAR) T cells, have become increasingly promising approaches to non-small-cell lung cancer (NSCLC) treatment. In this study, we explored the antitumor potential of prostate stem cell antigen (PSCA)-redirected CAR T and mucin 1 (MUC1)-redirected CAR T cells in tumor models of NSCLC. First, we generated patient-derived xenograft (PDX) mouse models of human NSCLC that maintained the antigenic profiles of primary tumors. Next, we demonstrated the expression of PSCA and MUC1 in NSCLC, followed by the generation and confirmation of the specificity and efficacy of PSCA- and MUC1-targeting CAR T cells against NSCLC cell lines in vitro. Finally, we demonstrated that PSCA-targeting CAR T cells could efficiently suppress NSCLC tumor growth in PDX mice and synergistically eliminate PSCA+MUC1+ tumors when combined with MUC1-targeting CAR T cells. Taken together, our studies demonstrate that PSCA and MUC1 are both promising CAR T cell targets in NSCLC and that the combinatorial targeting of these antigens could further enhance the antitumor efficacy of CAR T cells.