A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio.
A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio.
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针对与肿瘤相关的糖蛋白72的FAS配体（FASL）进行的人源化抗体选择性地表现出对较低的FASL/FAS比的口服癌细胞的细胞毒性作用。
DOI：
10.1158/1535-7163.mct-16-0314
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发表时间：
2017-06
影响因子：
5.7
通讯作者：
Hsiao M
中科院分区：
文献类型：
--
作者：
Chien MH;Chang WM;Lee WJ;Chang YC;Lai TC;Chan DV;Sharma R;Lin YF;Hsiao M
Fas配体（FasL）/Fas比值的表达改变直接影响肿瘤患者的预后，其在肿瘤细胞中的损伤可能导致细胞凋亡抵抗。因此，开发针对FasL/Fas系统的有效治疗方法可能在抗肿瘤治疗中发挥重要作用。在这项研究中，我们评估的融合蛋白（hcc 49 scFv-FasL）的细胞毒性结构域的FasL融合的人源化抗体（CC 49）对肿瘤相关糖蛋白72，这是在口腔鳞状细胞癌（OSCC）表达，是否可以选择性地杀死OSCC细胞与不同的FasL/Fas的比例。在临床标本中，与正常组织相比，肿瘤组织中FasL表达明显降低，Fas表达明显升高。FasL/Fas比值越低，OSCC患者的预后越差，OSCC细胞的增殖和侵袭能力越强。hcc 49 scFv-FasL对口腔鳞癌细胞（Cal-27和SAS）显示出选择性的细胞毒作用，但对正常口腔角质形成细胞（HOK）不显示通过凋亡诱导的细胞毒作用。此外，具有比Cal-27更低的FasL/Fas比率的SAS细胞对hcc 49 scFv-FasL的细胞毒性作用更敏感。与野生型FasL不同，hcc 49 scFv-FasL不被基质金属蛋白酶切割，也不诱导SAS细胞中的非凋亡信号。在体内，我们发现hcc 49 scFv-FasL在SAS原位和皮下异种移植肿瘤模型中显著减少淋巴结转移的形成并降低原发性肿瘤生长。总的来说，我们的数据表明，与FasL融合的肿瘤靶向抗体可以成为OSCC治疗的有力工具，特别是在FasL/Fas比值低的人群中。
Altered expression of the Fas ligand (FasL)/Fas ratio exhibits a direct impact on the prognosis of cancer patients, and its impairment in cancer cells may lead to apoptosis resistance. Thus, the development of effective therapies targeting the FasL/Fas system may play an important role in the flght against cancer. In this study, we evaluated whether a fusion protein (hcc49scFv-FasL) comprising of the cytotoxicity domain of the FasL fused to a humanized antibody (CC49) against tumor-associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios. In clinical samples, the significantly low FasL and high Fas transcripts were observed in tumors compared with normal tissues. A lower FasL/Fas ratio was correlated with a worse prognosis of OSCC patients and higher proliferative and invasive abilities of OSCC cells. The hcc49scFv-FasL showed a selective cytotoxic effect on OSCC cells (Cal-27 and SAS) but not on normal oral keratinocytes cells (HOK) through apoptosis induction. Moreover, SAS cells harboring a lower FasL/Fas ratio than Cal-27 were more sensitive to the cytotoxic effect of hcc49scFv-FasL. Unlike wild-type FasL, hcc49scFv-FasL was not cleaved by matrix metalloproteinases and did not induce nonapoptotic signaling in SAS cells. In vivo, we found that hcc49scFv-FasL drastically reduced the formation of lymph node metastasis and decreased primary tumor growth in SAS orthotopic and subcutaneous xenograft tumor models. Collectively, our data indicate that a tumor-targeting antibody fused to the FasL can be a powerful tool for OSCC treatment, especially in populations with a low FasL/Fas ratio.