Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL
Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL
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DOI：
10.4049/jimmunol.176.6.3402
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发表时间：
2006-03-15
影响因子：
4.4
通讯作者：
Ferris, Robert L.
中科院分区：
文献类型：
--
作者：
Lopez-Albaitero, Andres;Nayak, Jayakar V.;Ferris, Robert L.
尽管表达限制性 HLA I 类等位基因和靶向肿瘤 Ag (TA)，但头颈鳞状细胞癌 (SCCHN) 细胞在体外很难被 CTL 识别。多项证据表明，CTL 缺乏 SCCHN 细胞识别反映了由于 Ag 加工机制 (APM) 功能障碍，HLA I 类 Ag 向 CTL 呈递的靶向 TA 肽存在缺陷。首先，CTL 缺乏对 SCCHN 细胞的识别与 IFN-γ 诱导的 APM 成分低分子量的显着下调有关。蛋白 2、TAP1、TAP2 和 tapasin。其次，通过用外源靶向 TA 肽脉冲细胞来恢复 CTL 对 SCCHN 细胞的识别。第三，SCCHN 细胞与 IFN-γ 一起孵育后 CTL 识别的恢复与 APM 成分 TAP1、TAP2 和 Tapasin 的显着上调 (p = 0.001) 相关。最后也是最确定的一点是，通过转染野生型 TAP1 cDNA 可以恢复 CTL 对 SCCHN 细胞的识别。我们的研究结果可以解释 SCCHN 中 APM 成分下调与疾病临床病程不良之间的关联。此外，SCCHN细胞中APM缺陷的调节性质表明，病灶内施用IFN-γ可能对疾病的临床病程以及通过恢复CTL对SCCHN细胞的识别而对基于T细胞的SCCHN免疫疗法产生有益的影响。
Squamous cell carcinoma of the head and neck (SCCHN) cells are poorly recognized in vitro by CTL despite expressing the restricting HLA class I allele and the targeted tumor Ag (TA). Several lines of evidence indicate that the lack of SCCHN cell recognition by CTL reflects defects in targeted TA peptide presentation by HLA class I Ag to CTL because of Ag-processing machinery (APM) dysfunction. First, lack of recognition of SCCHN cells by CTL is associated with marked down-regulation of the IFN-gamma-inducible APM components low-m.w. protein 2, TAP1, TAP2, and tapasin. Second, SCCHN cell recognition by CTL is restored by pulsing cells with exogenous targeted TA peptide. Third, the restoration of CTL recognition following incubation of SCCHN cells with IFN-gamma is associated with a significant (p = 0.001) up-regulation of the APM components TAP1, TAP2, and tapasin. Lastly, and most conclusively, SCCHN cell recognition by CTL is restored by transfection with wild-type TAP1 cDNA. Our findings may explain the association between APM component down-regulation and poor clinical course of the disease in SCCHN. Furthermore, the regulatory nature of the APM defects in SCCHN cells suggests that intralesional administration of IFN-gamma may have a beneficial effect on the clinical course of the disease and on T cell-based immunotherapy of SCCHN by restoring SCCHN cell recognition by CTL.