Novel roles of STAT2 and IFN-I in tumorigenesis and responses to therapy

项目摘要 响应于I型干扰素（IFN-I）的刺激，STAT 2被JAK酪氨酸激酶磷酸化， 然后与磷酸化的STAT 1和IRF 9结合形成ISGF 3，ISGF 3驱动转录反应。这 STAT 2的典型功能对于对IFN-1的生物学应答是必不可少的，所述生物学应答是细胞抑制性的， 导致癌细胞中抗肿瘤免疫的激活。因此，STAT 2被认为有助于 抑制癌症进展和增强治疗。然而，STAT 2的这种原始观点受到了以下因素的挑战： 一些新的证据揭示了STAT 2以前未知的促肿瘤作用。更高水平的 STAT 2表达与肺癌预后不良和乳腺癌侵袭性表型相关 STAT 2缺陷可保护小鼠免受化学诱导的皮肤癌和结肠癌的侵害。但 STAT 2的这些促肿瘤活性的分子机制还没有很好地理解。帮助 为了弥合这一差距，我们已经确定了两种新的非典型的，促肿瘤活性的STAT 2，不需要 酪氨酸磷酸化首先，缺乏Y 690磷酸化的STAT 2（U-STAT 2）与IRF-9形成复合物， 即使没有IFN-1刺激。有趣的是，与ISGF 3不同，这种组成型U-STAT 2：IRF 9复合物 增加一组NFκ B依赖性基因（包括IL-6）的表达，促进 间充质/干细胞样表型。第二，U-STAT 2与胞质传感器STING结合， 防止STING刺激响应于DNA或cGAS的合成激动剂的IFN-I合成。这是 这是STAT 2功能的第一个例子，它完全独立于转录中的任何作用。值得注意的是， 这些非典型的STAT 2活性由以前未知的苏氨酸404的磷酸化调节 在STAT 2（小鼠中的T403）中，其促进U-STAT 2：IRF 9和U-STAT 2：STING复合物的形成。 因此，T404磷酸化STAT 2水平升高导致肺组织对顺铂的耐药性增加， 癌细胞和增强的肿瘤生长。此外，虽然P-T404 STAT 2水平在 人肺腺癌标本与减少的免疫细胞浸润、T403预防相关 在小鼠中通过T-to-A突变的磷酸化导致更好的肿瘤控制和增强的抗肿瘤免疫。 我们认为U-STAT 2的T404磷酸化促进了癌症的进展和对治疗的抵抗。 为了验证这一假设，我们将确定U-STAT 2在癌症进展中的肿瘤内在作用， 并研究T404调节的U-STAT 2/STING复合物在耐药性中的作用。 免疫疗法

Project Summary In response to stimulation by type I interferon (IFN-I), STAT2 is phosphorylated by JAK tyrosine kinases and then binds to phosphorylated STAT1 and IRF9 to form ISGF3, which drives the transcriptional response. This canonical function of STAT2 is indispensable for the biological responses to IFN-I, which are cytostatic and also lead to the activation of anti-tumor immunity in cancer cells. Consequently, STAT2 has been assumed to help suppress cancer progression and enhance therapy. However, this original view of STAT2 is challenged by several new lines of evidence that reveal a previously unknown pro-tumor impact of STAT2. A higher level of STAT2 expression is associated with a worse prognosis in lung cancer and an aggressive phenotype in breast cancer, and STAT2 deficiency protects mice from chemically induced skin and colon cancer. However, the molecular mechanisms underlying these pro-tumor activities of STAT2 are not yet well understood. Helping to bridge this gap, we have identified two novel non-canonical, pro-tumor activities of STAT2 that do not require tyrosine phosphorylation. First, STAT2 lacking phosphorylation of Y690 (U-STAT2) forms a complex with IRF-9, even in the absence of IFN-I stimulation. Intriguingly, unlike ISGF3, this constitutive U-STAT2:IRF9 complex increases the expression of a set of NFκB-dependent genes, including IL-6, facilitating the development of a mesenchymal/stem-like phenotype in lung cancer cells. Second, U-STAT2 binds to the cytosolic sensor STING, preventing STING from stimulating IFN-I synthesis in response to DNA or synthetic agonists of cGAS. This is the first example of a STAT2 function that is completely independent of any role in transcription. Notably, both these non-canonical STAT2 activities are regulated by a previously unknown phosphorylation of threonine 404 in STAT2 (T403 in mice), which promotes the formation of U-STAT2:IRF9 and U-STAT2:STING complexes. Consequently, elevated level of T404 phosphorylated STAT2 result in increased resistance to cisplatin in lung cancer cells and enhanced tumor growth in a xenograft model. Furthermore, while the level of P-T404 STAT2 in human lung adenocarcinoma specimens correlates with reduced immune cell infiltration, prevention of T403 phosphorylation by a T-to-A mutation in mice leads to better tumor control and enhanced anti-tumor immunity. We propose that the T404 phosphorylation of U-STAT2 promotes cancer progression and resistance to therapy. To test this hypothesis, we will determine the tumor-intrinsic roles of U-STAT2 in cancer progression and chemoresistance; and investigate the role of the T404-regulated U-STAT2/STING complex in resistance to immunotherapy.