CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30(+) and CD30(-) Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions.
CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30(+) and CD30(-) Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions.
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通过CD30重新定义的嵌合抗原受体T细胞靶向CD30（+）和CD30（ - ）胚胎癌通过抗原依赖性和FAS/FASL相互作用。
DOI：
10.1158/2326-6066.cir-18-0065
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发表时间：
2018-10
影响因子：
10.1
通讯作者：
Savoldo B
中科院分区：
文献类型：
--
作者：
Hong LK;Chen Y;Smith CC;Montgomery SA;Vincent BG;Dotti G;Savoldo B
肿瘤抗原异质性限制了嵌合抗原受体（CAR） t细胞治疗的成功。含有EC的胚胎癌（ECs）和混合睾丸生殖细胞肿瘤（TGCT）是最具侵袭性的TGCT亚型，由于ECs表达CD30抗原，但也含有CD30 - /dim细胞，因此有助于解剖这一问题。我们发现CD30重定向CAR - T细胞(CD30。CAR - T细胞在体外对人EC细胞系Tera-1、Tera-2和NCCIT以及经Hoechst染色鉴定的推定EC干细胞表现出抗肿瘤活性。CD30的细胞溶解活性。CAR - T细胞的持续增殖和促炎细胞因子的产生是补充。CD30。CAR - T细胞在转移性EC的体内异种移植NSG小鼠模型中也显示出抗肿瘤活性。我们观察到CD30。CAR - T细胞在通过CAR靶向CD30+ EC肿瘤细胞（即抗原依赖性靶向）的同时，也通过细胞-细胞接触依赖性Fas/FasL相互作用以抗原不依赖的方式消除周围的CD30 - EC细胞。此外，CD30+ Fas - EC中异位Fas （CD95）的表达足以改善CD30。CAR - t细胞抗肿瘤活性。总的来说，这些数据表明CD30。CAR - T细胞可能是一种有效的内皮细胞免疫疗法。此外，肿瘤细胞和CAR - T细胞之间的Fas/FasL相互作用可以减少由于异质抗原表达引起的肿瘤逃逸或提高CAR - T细胞抗肿瘤活性。
Tumor antigen heterogeneity limits success of chimeric antigen receptor (CAR) T-cell therapies. Embryonal carcinomas (ECs) and mixed testicular germ cell tumors (TGCTs) containing EC, which are the most aggressive TGCT subtypes, are useful for dissecting this issue as ECs express the CD30 antigen but also contain CD30–/dim cells. We found that CD30-redirected CAR T cells (CD30.CAR T cells) exhibit antitumor activity in vitro against the human EC cell lines Tera-1, Tera-2 and NCCIT, and putative EC stem cells identified by Hoechst dye staining. Cytolytic activity of CD30.CAR T cells was complemented by their sustained proliferation and pro-inflammatory cytokine production. CD30.CAR T cells also demonstrated antitumor activity in an in vivo xenograft NSG mouse model of metastatic EC. We observed that CD30.CAR T cells, while targeting CD30+ EC tumor cells through the CAR (i.e. antigen-dependent targeting), also eliminated surrounding CD30– EC cells in an antigen-independent manner, via cell-cell contact-dependent Fas/FasL interaction. In addition, ectopic Fas (CD95) expression in CD30+ Fas– EC was sufficient to improve CD30.CAR T-cell antitumor activity. Overall, these data suggest that CD30.CAR T cells might be useful as an immunotherapy for ECs. Additionally, Fas/FasL interaction between tumor cells and CAR T cells can be exploited to reduce tumor escape due to heterogeneous antigen expression or to improve CAR T-cell antitumor activity.