干扰素通路（IFNs/JAK/STAT）异常是肿瘤免疫逃逸重要机制之一。我们已经发现黑色素瘤以及黑色素瘤病人的外周血淋巴细胞IFN/JAK/STAT均异常，且两者呈正相关；并证明了黑色素瘤细胞NOS1抑制免疫细胞IFN/JAK/STAT功能，由此，我们推测NOS1也是黑色素瘤自身IFN/JAK/STAT异常的机制。为验证假说，本项目拟 1）沉默或过表达NOS1，体内外实验探讨NOS1对黑色素瘤IFN/JAK/STAT 的作用，进而研究NOS1与JAK1磷酸化的相互关系，探讨NOS1 调控IFN/JAK/STAT的分子机制； 2）用裸鼠肿瘤模型观察NOS1抑制后对黑色素瘤IFNa治疗的增敏效果；3）临床资料和芯片数据分析NOS1和JAK1与黑色素瘤免疫治疗预后的关系。据此，明确黑色素瘤NOS1对IFN/JAK/STAT的作用和机制，为黑色素瘤的免疫治疗提出新的靶点和预后指标。

IFN/JAK/STAT controls the immune response. We found that dysfunction of IFN signal had been documented in melanoma and coresponding PBMC, and both of dysfunction were correlated. Moreover,the melanoma NOS1 produce NO to inhibit IFN signal function in PBMCs. However, it is not known whether melanoma NOS1 expression is responsible for the dysfunction of IFN signal and whether the dysfuntion is contribute to the IFNa therapy resistance in melanoma. Here, we study the relationship of NOS1 expression and IFNa response in melanoma. To uncover the NOS1 inhibition on IFN/JAK/STAT, we investigate relationship of NOS1 expression and JAK1 phosphorylation. Further more, we study whether NOS1 management could improve the outcome of melanoma IFNa treatment through melanoma xenograph mode. Finally, we explore the progrosis and diagnosis meaning of NOS1 and its target JAK1 on immune therapy of melanoma, through analyzing the relationship between clinical data of melanoma immune therapy and the melanoma NOS1 and JAK1 expression evaluated by expression array. Therefore, this project is expected to study the mechanism of IFNsignal dysfunction in melanoma and present its clinical meaning by providing NOS1 and JAK1 as new biomarkers for melanoma targeting therapy and prognosis.