An epithelial cell adhesion molecule- and CD3-bispecific antibody plus activated T-cells can eradicate chemoresistant cancer stem-like pancreatic carcinoma cells in vitro.
An epithelial cell adhesion molecule- and CD3-bispecific antibody plus activated T-cells can eradicate chemoresistant cancer stem-like pancreatic carcinoma cells in vitro.
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发表时间：
2014-08
影响因子：
2
通讯作者：
Masayo Umebayashi;Akifumi Kiyota;Norihiro Koya;Hiroto Tanaka;H. Onishi;M. Katano;T. Morisaki
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文献类型：
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作者：
Masayo Umebayashi;Akifumi Kiyota;Norihiro Koya;Hiroto Tanaka;H. Onishi;M. Katano;T. Morisaki
胰腺癌是肿瘤中侵袭性最强的一种类型，它与肿瘤的转移、侵袭和治疗耐药密切相关。更重要的是，肿瘤干细胞(CSLCs)的化疗耐药是根除胰腺癌的关键问题。CD44和上皮细胞黏附分子(EpCAM)等细胞表面标志物是胰腺癌CSLC的分子靶点。在这项研究中，我们研究了Catumaxomab，一种与肿瘤细胞上的EpCAM和T细胞上的CD3结合的临床级双特异性抗体，与激活的T细胞相结合，能否在体外消除化疗耐药的胰腺CSLCs。首先，我们从人胰腺癌细胞中建立了CSLC细胞系(MU-PK1)，该细胞来源于一例化疗耐药和播散性胰腺癌患者。这些CSLC对10μg/ml浓度的吉西他滨介导的细胞毒几乎完全耐受。这些细胞表达高水平的CSLC标志物(CD44和EpCAM)，并具有明显更高的球体形成、侵袭和乙醛脱氢酶-1表达能力，这与癌症的干细胞特性有关。我们发现，Catumaxomab预处理和随后加入IL-2/OKT3激活的自体T细胞在短时间内消除CSLCs。此外，当MU-PK1细胞在低氧条件下培养时，CSLCs的侵袭性变得更强。然而，细胞因子激活的杀伤T细胞与Catumaxomab的结合成功地裂解了几乎所有这些细胞。综上所述，Catumaxomab联合活化的T细胞可能是根除耐药的胰腺CSLC的一种有效的治疗方法。
Cancer stem-like properties of various types of cancer, including pancreatic cancer, one of the most aggressive types, correlate with metastasis, invasion, and therapeutic resistance. More importantly, chemoresistance in cancer stem-like cells (CSLCs) is a critical problem for eradication of pancreatic cancer. Several cell surface markers, such as CD44 and epithelial cell adhesion molecule (EpCAM), are molecular targets on CSLCs of pancreatic carcinoma. In this study, we investigated whether catumaxomab, a clinical-grade bi-specific antibody that binds to both EpCAM on tumor cells and CD3 on T-cells, combined with activated T-cells can eliminate chemoresistant pancreatic CSLCs in vitro. Firstly, we established a CSLC line (MU-PK1) from human pancreatic carcinoma cells derived from a patient with chemoresistant and disseminated pancreatic cancer. These CSLCs were almost completely resistant to gemcitabine-mediated cytotoxicity up to a concentration of 10 μg/ml. The cells expressed high levels of CSLC markers (CD44 and EpCAM) and had significantly higher capacities for sphere formation, invasion, and aldehyde dehydrogenase-1 expression, which are associated with cancer stemness properties. We found that pre-treatment with catumaxomab and subsequent addition of interleukin-2/OKT3 activated autologous T-cells eliminated CSLCs during a short incubation period. Moreover, when MU-PK1 cells were cultured under hypoxic conditions, the CSLCs became more aggressive. However, the combination of cytokine-activated killer T-cells with catumaxomab successfully lysed almost all these cells. In conclusion, catumaxomab combined with activated T-cells may be a potent therapeutic modality to eradicate chemoresistant pancreatic CSLCs.