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

STAT2 和 IFN-I 在肿瘤发生和治疗反应中的新作用

• 批准号: 10493938
• 负责人: GEORGE ROBERT STARK
• 金额: $ 48.36万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493938
• 关键词: A549; Adjuvant; Affect; Agonist; Alanine; Animal Model; Antitumor Response; Automobile Driving; Binding; Biological; Biopsy; Breast Cancer Cell; Cancer Cell Growth; Cancer Control; Cancer Model; Cancer Patient; Cell Death; Cells; Chemicals; Chemoresistance; Cisplatin; Colon Carcinoma; Complex; Cytostatics; Cytotoxic T-Lymphocytes; DNA; Data; Development; Dissection; Epithelial; Evaluation; Failure; Gene Expression; Genes; Genetic Transcription; Growth; Human; ISGF3G protein; Immune; Immunotherapy; In Vitro; Infiltration; Interferon Type I; Interferon-beta; Interferons; Interleukin-17; Interleukin-6; Knock-in Mouse; Knowledge; Lead; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mesenchymal; Mesenchymal Stem Cells; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Outcome; Phenotype; Phosphorylation; Phosphotransferases; Play; Prevention; Production; Prognosis; Property; Protein Tyrosine Kinase; Regulatory Pathway; Resistance; Role; STAT1 gene; STAT2 gene; STAT3 gene; STING agonists; Skin; Skin Cancer; Specimen; Standardization; Stimulator of Interferon Genes; TBK1 gene; Testing; Therapeutic; Therapeutic Intervention; Threonine; Tumor Immunity; Tyrosine Phosphorylation; Work; Xenograft Model; Xenograft procedure; anti-PD-1; base; cancer cell; cancer immunotherapy; cancer therapy; chemotherapeutic agent; chemotherapy; colon tumorigenesis; cytokine; improved; in vivo; in vivo Model; interferon-stimulated gene factor 3; lung cancer cell; malignant breast neoplasm; mimetics; novel; novel strategies; prevent; programs; response; sensor; stem; stem cell biomarkers; stem-like cell; therapy resistant; transcription factor; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

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.

项目概要 响应 I 型干扰素 (IFN-I) 的刺激，STAT2 被 JAK 酪氨酸激酶磷酸化， 然后与磷酸化的 STAT1 和 IRF9 结合形成 ISGF3，驱动转录反应。 STAT2 的典型功能对于 IFN-I 的生物反应是不可或缺的，IFN-I 具有细胞抑制作用，并且 STAT2 被认为有助于激活癌细胞中的抗肿瘤免疫。 抑制癌症进展并增强治疗然而，STAT2 的这种原始观点受到了挑战。 一些新的证据表明 STAT2 具有更高水平的促肿瘤作用。 STAT2 表达与肺癌预后较差和乳腺癌侵袭性表型相关 癌症，STAT2 缺陷可以保护小鼠免受化学诱发的皮肤癌和结肠癌。 STAT2 的这些促肿瘤活性的分子机制尚不清楚。 为了弥补这一差距，我们已经确定了 STAT2 的两种新颖的非典型促肿瘤活性，它们不需要 首先，缺乏 Y690 磷酸化的 STAT2 (U-STAT2) 与 IRF-9 形成复合物， 有趣的是，与 ISGF3 不同的是，即使在没有 IFN-I 刺激的情况下，这种组成型 U-STAT2:IRF9 复合物也能发挥作用。 增加一组 NFκB 依赖性基因（包括 IL-6）的表达，促进 其次，U-STAT2 与细胞质传感器 STING 结合。 阻止 STING 刺激 IFN-I 合成以响应 DNA 或合成的 cGAS 激动剂。 STAT2 功能的第一个例子完全独立于转录中的任何作用。 这些非经典的 STAT2 活性是由先前未知的苏氨酸磷酸化调节的 第404章 STAT2（小鼠中的 T403），促进 U-STAT2:IRF9 和 U-STAT2:STING 复合物的形成。 检查发现，T404 磷酸化 STAT2 水平升高导致肺部对顺铂的耐药性增加 此外，在异种移植模型中，P-T404 STAT2 的水平也有所提高。 人肺腺癌标本与免疫细胞浸润减少、T403 预防相关 小鼠中 T 至 A 突变导致的磷酸化可更好地控制肿瘤并增强抗肿瘤免疫力。 我们认为 U-STAT2 的 T404 磷酸化会促进癌症进展和对治疗的抵抗。 为了验证这一假设，我们将确定 U-STAT2 在癌症进展中的肿瘤内在作用，以及 化学耐药性；并研究 T404 调节的 U-STAT2/STING 复合物在耐药性中的作用 免疫疗法。