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

项目摘要 作为对I型干扰素(IFN-I)刺激的反应，STAT2被JAK酪氨酸激酶和 然后与磷酸化的STAT1和IRF9结合形成ISGF3，从而驱动转录反应。这 STAT2的典型功能对于干扰素-I的生物反应是不可或缺的，这是细胞抑制的，也是 导致癌细胞中抗肿瘤免疫的激活。因此，STAT2被认为是有帮助的 抑制癌症进展，加强治疗。然而，这种对STAT2的原始观点受到了以下挑战 几条新的证据揭示了以前未知的STAT2促进肿瘤的影响。更高水平的 STAT2表达与肺癌预后不良和乳腺侵袭性表型有关 STAT2缺乏可保护小鼠免受化学诱导的皮肤癌和结肠癌。然而， STAT2这些促肿瘤活性的分子机制还不是很清楚。帮助 弥补这一差距，我们已经确定了两个新的非规范的、促肿瘤的STAT2活性，它们不需要 酪氨酸磷酸化。首先，缺乏Y690磷酸化的STAT2(U-STAT2)与IRF-9形成络合物， 即使在没有干扰素-I刺激的情况下。有趣的是，与ISGF3不同的是，这个结构性的U-STAT2：IRF9复合体 增加一组依赖于核因子κB的基因的表达，包括IL-6，促进 肺癌细胞间充质/干细胞性表型。第二，U-STAT2与胞质传感器刺突结合， 防止刺痛刺激干扰素-I的合成，以回应DNA或cGAS的合成激动剂。这是 STAT2功能的第一个例子，它完全独立于转录中的任何角色。值得注意的是，两者 这些非规范的STAT2活性由苏氨酸404的一种未知的磷酸化来调节 在STAT2(小鼠T403)中，促进U-STAT2：IRF9和U-STAT2：STING复合体的形成。 因此，T404磷酸化的STAT2水平升高导致肺对顺铂的耐药性增加 在异种移植模型中癌细胞和促进肿瘤生长。此外，虽然P-T404 STAT2水平在 人肺腺癌标本与免疫细胞浸润减少及T403的预防作用 小鼠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-STAT2的T404磷酸化促进了肿瘤的进展和对治疗的抵抗。 为了验证这一假说，我们将确定U-STAT2在肿瘤进展和肿瘤进展中的内在作用。 并研究T404调节的U-STAT2/STING复合体在抗药性中的作用 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.