T细胞老化标记物CD57快速有效从胶质瘤干细胞转移到CAR-T细胞

Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells.

T细胞老化标记物CD57快速有效的从胶质瘤干细胞转移到CAR-T细胞

摘要:
嵌合抗原受体修饰的T细胞过继治疗为癌症的治疗带来很大的希望。我们最近开发了一种靶向 原癌干细胞标记物AC133的嵌合抗原受体修饰的T细胞，显示了这些CAR-T 细胞能够在体内杀死ACC-133表达阳性的胶质瘤干细胞（GBM-SCs），而且能够抑制异种移植小鼠体内胶质瘤干细胞（GBM-SCs）诱导产生的脑肿瘤。通过和GBM-SCs共培养，我们发现T细胞老化标记物明显上调，但是其他与终端T细胞分化的表型和功能变化不能够立即检测到。这里，我们提供的证据表明CD57迅速高效的从CD57阳性GBM-SCs转移到预先活化的T细胞上，而且这种转移被特异性CAR/配体相互作用而大大增强。从CD57阳性肿瘤细胞分离后，CD57抗原决定簇在T细胞表面的表达在随后的几天会慢慢减少。我们判断，CD57从肿瘤细胞转移到T细胞可能只会发生在CD57阳性病人的体内，可能我们也需要考虑肿瘤浸润淋巴细胞表型分析的结果，以及肿瘤、淋巴结内或者外周血单个核细胞来源的肿瘤特异性T 细胞的特性。

ABSTRACT
Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) holds great promise for cancer treatment. We recently developed CAR T cells targeting the prototypic cancer stem cell marker AC133 and showed that these CAR T cells killed AC133+ glioblastoma stem cells (GBM-SCs) in vitro and inhibited the growth of brain tumors initiated from GBM-SCs in xenograft mouse models in vivo. Upon coincubation with GBM-SCs, we observed strong upregulation of the T cell aging marker CD57, but other phenotypical or functional changes usually associated with terminal T cell differentiation could not immediately be detected. Here, we provide evidence suggesting that CD57 is rapidly and efficiently transferred from CD57+ GBM-SCs to preactivated T cells and that the transfer is greatly enhanced by specific CAR/ligand interaction. After separation from CD57+ tumor cells, CD57 epitope expression on T cells decreased only slowly over several days. We conclude that CD57 transfer from tumor cells to T cells may occur in patients with CD57+ tumors and that it may have to be considered in the interpretation of phenotyping results for tumor-infiltrating lymphocytes and perhaps also in the characterization of tumor-specific T cells from tumor or lymph node homogenates or peripheral blood mononuclear cells.