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.

项目摘要 为了响应I型干扰素刺激（IFN-I），STAT2被JAK酪氨酸激酶和 然后与磷酸化的STAT1和IRF9结合形成ISGF3，从而驱动转录响应。这 STAT2的规范功能对于对IFN-I的生物学反应是必不可少的，IFN-I是细胞抑制的，也是 导致癌细胞中抗肿瘤免疫学的激活。因此，已假定STAT2有帮助 抑制癌症进展并增强治疗。但是，STAT2的原始观点受到挑战 几条新的证据揭示了STAT2先前未知的肿瘤影响。更高的水平 STAT2表达与肺癌的预后较差和乳房的侵略性表型有关 癌症和STAT2缺乏可保护小鼠免受化学诱导的皮肤和结肠癌的侵害。但是， STAT2这些促肿瘤活性背后的分子机制尚不清楚。帮助 桥梁这一差距，我们已经确定了STAT2的两个新型非典型的肿瘤活动，它们不需要 酪氨酸磷酸化。首先，缺乏Y690（U-STAT2）磷酸化的STAT2与IRF-9形成复合物， 即使没有IFN-I刺激。有趣的是，与ISGF3不同，本构型U-STAT2：IRF9复合物 增加了一组NFκB依赖性基因的表达，包括IL-6，支持A的发展 肺癌细胞中的间充质/茎状表型。其次，U-STAT2与胞质传感器刺激结合， 防止刺激刺激IFN-I合成，以响应CGA的DNA或合成激动剂。这是 STAT2函数的第一个示例完全独立于转录中的任何角色。值得注意的是 这些非典型的STAT2活性受到先前未知的苏氨酸磷酸化的调节 在STAT2（小鼠中T403）中，促进了U-STAT2：IRF9和U-STAT2：STING复合物的形成。 因此，T404磷酸化的STAT2水平升高导致对肺中对顺铂的抗性增加 异种移植模型中的癌细胞并增强了肿瘤生长。此外，虽然P-T404 STAT2的水平 人肺腺癌的规格与免疫栓塞浸润降低相关，预防T403 小鼠中T-TO-A突变磷酸化会导致更好的肿瘤控制和增强的抗肿瘤免疫力。 我们建议U-STAT2的T404磷酸化促进癌症的进展和对治疗的抵抗力。 为了检验这一假设，我们将确定U-STAT2在癌症进展和 化学抗性；并研究T404调节的U-STAT2/STING复合物在抗性中的作用 免疫疗法。