2016年1月11日 訊 /生物谷BIOON/--樹突狀細胞（DC）是調節宿主免疫反應的關鍵中間環節，包括免疫激活也包括免疫耐受。同時，DC也被發現能夠調節宿主的抗腫瘤免疫反應。因此，了解腫瘤細胞是如何激活宿主的DC並由此產生特異性的免疫反應對於理解這一過程至關重要。
近年來，越來越多的證據表明在黑色素瘤患者體內檢測到了抗腫瘤特異性免疫反應。然而，從腫瘤組織或腫瘤附近的淋巴結中分離得到的腫瘤特異性效應T細胞都缺少活性。因此，很多人認為，腫瘤組織分泌的某些特定因子可能會對宿主的免疫系統產生影響，從而使T細胞的活性受到抑制。對此，來自美國Hampden-Sydney學院的Osric A Forrest課題組分析了腫瘤相關因子對宿主DC的成熟以及激活的影響，從而進一步調節宿主免疫反應的內在機制。結果發表在最近一期的《immunology and cell biology》雜誌上。
首先，作者收集了培養黑色素瘤組織的培養基（推定其內部含有腫瘤相關因子），並利用該培養液對脾臟DC進行刺激，並輔以LPS的刺激。結果顯示：LPS能夠引起DC表面CD80與CD86的表達量的上升，但B16黑色素瘤的培養液刺激則能夠顯著下調LPS對DC的影響。然而，DC表面其他負向調節因子的表達卻沒有顯著改變。這說明B16黑色素瘤分泌的某些因子能夠抑制DC的激活。
之後，作者對黑色素瘤細胞的免疫調節相關基因表達譜進行了檢測。結果顯示，黑色素瘤細胞內部TGF-b與VEGF-C的表達量較高。之後，作者利用shRNA的方法下調了腫瘤細胞中這兩類因子的表達水平。結果顯示，shRNA處理之後的腫瘤細胞培養液不再具有抑制DC激活的作用。之後，作者檢測了這部分受到腫瘤細胞影響的DC在傳遞信號方面的功能。結果表明，雖然DC的激活受到了部分影響，但這部分DC依然具有激活CD8 T細胞的功能。
最後，作者通過體內注射腫瘤細胞的方法驗證了腫瘤相關因子在生理狀態下對DC的調節作用。結果顯示，在小鼠注射一定數量的B16黑色素瘤細胞後，肺部出現大量的巨噬細胞聚集，同時腫瘤的生長也因此受到了正反饋調節。（生物谷Bioon.com）
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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.