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肿瘤组织分泌细胞因子调节DC的成熟

来源:生物谷 2016-01-11 16:33

2016年1月11日 讯 /生物谷BIOON/--树突状细胞(DC)是调节宿主免疫反应的关键中间环节,包括免疫激活也包括免疫耐受。同时,DC也被发现能够调节宿主的抗肿瘤免疫反应。因此,了解肿瘤细胞是如何激活宿主的DC并由此产生特异性的免疫反应对于理解这一过程至关重要。

近年来,越来越多的证据表明在黑色素瘤患者体内检测到了抗肿瘤特异性免疫反应。然而,从肿瘤组织或肿瘤附近的淋巴结中分离得到的肿瘤特异性效应T细胞都缺少活性。因此,很多人认为,肿瘤组织分泌的某些特定因子可能会对宿主的免疫系统产生影响,从而使T细胞的活性受到抑制。对此,来自美国Hampden-Sydney学院的Osric A Forrest课题组分析了肿瘤相关因子对宿主DC的成熟以及激活的影响,从而进一步调节宿主免疫反应的内在机制。结果发表在最近一期的《immunology and cell biology》杂志上。
 
首先,作者收集了培养黑色素瘤组织的培养基(推定其内部含有肿瘤相关因子),并利用该培养液对脾脏DC进行刺激,并辅以LPS的刺激。结果显示:LPS能够引起DC表面CD80与CD86的表达量的上升,但B16黑色素瘤的培养液刺激则能够显著下调LPS对DC的影响。然而,DC表面其他负向调节因子的表达却没有显著改变。这说明B16黑色素瘤分泌的某些因子能够抑制DC的激活。
 
之后,作者对黑色素瘤细胞的免疫调节相关基因表达谱进行了检测。结果显示,黑色素瘤细胞内部TGF-b与VEGF-C的表达量较高。之后,作者利用shRNA的方法下调了肿瘤细胞中这两类因子的表达水平。结果显示,shRNA处理之后的肿瘤细胞培养液不再具有抑制DC激活的作用。之后,作者检测了这部分受到肿瘤细胞影响的DC在传递信号方面的功能。结果表明,虽然DC的激活受到了部分影响,但这部分DC依然具有激活CD8 T细胞的功能。
 
最后,作者通过体内注射肿瘤细胞的方法验证了肿瘤相关因子在生理状态下对DC的调节作用。结果显示,在小鼠注射一定数量的B16黑色素瘤细胞后,肺部出现大量的巨噬细胞聚集,同时肿瘤的生长也因此受到了正反馈调节。(生物谷Bioon.com)
 

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PMID:
 
Melanoma-derived factors alter the maturation and activation of differentiated tissue-resident dendritic cells
 
Kristian M Hargadon, Johnathan D Bishop, John P Brandt, Zachary C Hand, Yonathan T Ararso1 and Osric A Forrest
 
Dendritic cells (DCs) are key regulators of host immunity that are capable of inducing either immune tolerance or activation. In addition to their well-characterized role in shaping immune responses to foreign pathogens, DCs are also known to be critical for the induction and maintenance of anti-tumor immune responses. Therefore, it is important to understand how tumors influence the function of DCs and the quality of immune responses they elicit. Although the majority of studies in this field to date have utilized either immortalized DC lines or DC populations that have been generated under artificial conditions from hematopoietic precursors in vitro, we wished to investigate how tumors impact the function of already differentiated, tissue-resident DCs. Therefore, we used both an ex vivo and in vivo model system to assess the influence of melanoma-derived factors on DC maturation and activation. In ex vivo studies with freshly isolated splenic DCs, we demonstrate that the extent to which DC maturation and activation are altered by these factors correlates with melanoma tumorigenicity, and we identify partial roles for tumor-derived transforming growth factor (TGF)β1 and vascular endothelial growth factor (VEGF)-A in the altered functionality of DCs. In vivo studies using a lung metastasis model of melanoma also demonstrate tumorigenicity-dependent alterations to the function of lung-resident DCs, and skewed production of proinflammatory cytokines and chemokines by these tumor-altered cells is associated with recruitment of an immune infiltrate that may ultimately favor tumor immune escape and outgrowth.
 
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