Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes.
Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes.
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DOI：
10.1007/s00262-010-0961-7
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Ferris RL
中科院分区：
文献类型：
--
作者：
Leibowitz MS;Andrade Filho PA;Ferrone S;Ferris RL
头颈部鳞状细胞癌（SCCHN）细胞可通过下调抗原加工机制（APM）组分（如与抗原加工相关的转运蛋白（TAP）-1/2异二聚体）逃避肿瘤抗原（TA）特异性细胞毒性T淋巴细胞（CTL）的识别。干扰素γ（IFN-γ）上调APM组分可恢复SCCHN细胞识别和对CTL裂解的敏感性，但SCCHN细胞中TAP 1/2下调的潜在机制尚不清楚。由于IFN-γ激活信号转导和转录激活因子（STAT）-1，我们研究了磷酸化（p）-STAT 1作为SCCHN细胞中低基础TAP 1/2表达的介导物。发现SCCHN细胞表达基础总STAT1，但低至不可检测水平的活化STAT1。增加的pSTAT1水平和APM组分的关联可能反映了因果关系，因为STAT1敲低显著降低了IFN-γ处理的SCCHN细胞的IFN-γ介导的APM组分表达和TA特异性CTL识别。另一方面，由于致癌pSTAT3在SCCHN细胞中过表达，并发现与pSTAT1异源二聚体化，我们还测试了pSTAT3和pSTAT1：pSTAT3异源二聚体是否抑制IFN-γ诱导的STAT1活化和APM组分表达。首先，STAT3激活或缺失不影响基础或IFN-γ诱导的pSTAT1和APM组分的表达或TA特异性CTL对SCCHN细胞的识别。第二，pSTAT1：pSTAT3异二聚体不干扰IFN-γ诱导的STAT1与TAP 1启动子的结合或APM蛋白表达。这些发现表明APM组分下调主要由IFN-γ-pSTAT1介导的信号通路调节，不依赖于SCCHN细胞中致癌性STAT3过表达。
Squamous cell carcinoma of the head and neck (SCCHN) cells can escape recognition by tumor antigen (TA)-specific cytotoxic T lymphocytes (CTL) by downregulation of antigen processing machinery (APM) components, such as the transporter associated with antigen processing (TAP)-1/2 heterodimer. APM component upregulation by interferon gamma (IFN-γ) restores SCCHN cell recognition and susceptibility to lysis by CTL, but the mechanism underlying TAP1/2 downregulation in SCCHN cells is not known. Because IFN-γ activates signal transducer and activator of transcription (STAT)-1, we investigated phosphorylated (p)-STAT1 as a mediator of low basal TAP1/2 expression in SCCHN cells. SCCHN cells were found to express basal total STAT1 but low to undetectable levels of activated STAT1. The association of increased pSTAT1 levels and APM components likely reflects a cause–effect relationship, since STAT1 knockdown significantly reduced both IFN-γ-mediated APM component expression and TA-specific CTL recognition of IFN-γ-treated SCCHN cells. On the other hand, since oncogenic pSTAT3 is overexpressed in SCCHN cells and was found to heterodimerize with pSTAT1, we also tested whether pSTAT3 and pSTAT1:pSTAT3 heterodimers inhibited IFN-γ-induced STAT1 activation and APM component expression. First, STAT3 activation or depletion did not affect basal or IFN-γ-induced expression of pSTAT1 and APM components or recognition of SCCHN cells by TA-specific CTL. Second, pSTAT1:pSTAT3 heterodimers did not interfere with IFN-γ-induced STAT1 binding to the TAP1 promoter or APM protein expression. These findings demonstrate that APM component downregulation is regulated primarily by an IFN-γ-pSTAT1-mediated signaling pathway, independent of oncogenic STAT3 overexpression in SCCHN cells.
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DOI：
10.1097/cji.0b013e3181b8f421
发表时间：
2010-01
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Andrade Filho PA;López-Albaitero A;Gooding W;Ferris RL
通讯作者：
Ferris RL
影响因子：
56.9
作者：
HOSKEN, NA;BEVAN, MJ
通讯作者：
BEVAN, MJ
影响因子：
11.5
作者：
Meissner, M;Reichert, TE;Seliger, B
通讯作者：
Seliger, B
影响因子：
3.8
作者：
Lathers, DMR;Young, MRI
通讯作者：
Young, MRI
影响因子：
5.8
作者：
Andrade Filho, Pedro A.;Ito, Daisuke;Ferris, Robert L.
通讯作者：
Ferris, Robert L.