Project 3- Integrated Stress and Interferon Responses

项目 3 - 综合压力和干扰素反应

• 批准号: 10017915
• 负责人: Serge Y Fuchs
• 金额: $ 29.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017915
• 关键词: ARNTL gene; Adoptive Transfer; Affect; Affinity; Attenuated; Benign; Bypass; Cell Proliferation; Cells; Cessation of life; Complement; Cytotoxic T-Lymphocytes; Data; Development; Down-Regulation; Funding; Generations; Genes; Genetic; Genetic Translation; IFNAR1 gene; Immune; Immune checkpoint inhibitor; Immune response; Immunologic Surveillance; Immunotherapy; Interferon Type I; Interferon-alpha; Interferons; Interleukin-2; Knowledge; Ligands; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Mediating; MicroRNAs; Mus; Pathway interactions; Play; Protein Biosynthesis; Recombinants; Resistance; Role; Signal Transduction; Stabilizing Agents; Stress; Stress Response Signaling; T cell therapy; Testing; Translations; Tumor Escape; Tumor Immunity; Work; anti-cancer; base; biological adaptation to stress; cancer cell; cancer therapy; chimeric antigen receptor T cells; cytokine; cytotoxic; experimental study; improved; improved outcome; in vivo; innovation; metabolomics; mouse model; neoplastic cell; novel; p38 Mitogen Activated Protein Kinase; receptor; response; restoration; therapy outcome; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

ABSTRACT Development and progression of cancer occurs in spite of anti-tumorigenic effects of Type 1 interferon cytokines (IFN1, including IFNα and IFNβ). IFN1 counteract tumor development and progression directly (by suppression of malignant cells) and indirectly (by stimulation of anti-tumor immunity). Our work in the past funding period revealed that the integrated stress response (ISR) induced in the tumor microenvironment help malignant and benign tumor cells to evade the anti-tumorigenic effects of IFN1. We found that ISR-driven inactivation of IFN1 receptor IFNAR1 deprives tumor cells from ability to respond to IFN1 and plays an important role in tumor growth and progression. Furthermore, our work revealed an important role of IFNAR1 inactivation in the ISR-induced death of activated intra-tumoral cytotoxic T lymphocytes and, accordingly, in generation of the immune privileged niche that helps to overcome anti-tumor immunity. Our new pilot experiments also suggested that inactivation of IFNAR1 decreases the tumoricidal activity of cytotoxic T lymphocytes and undermines the efficacy of adoptive transfer of chimeric antigen receptor T cells and of inhibitors of immune checkpoints. New preliminary studies from our group and our collaborators (Projects 1-2) also revealed that additional innovative mechanisms promoting tumorigenesis depend on inactivation of the IFNAR1 pathway in a manner that involve ATF4 and its regulated miRNAs (e.g. miR-211 and miR-217) and include the suppression of translation of the mRNAs for IFNAR1 and the IFN-stimulated genes (IGSs). In our current proposal, we aim to define these mechanisms and target them to augment anti-cancer therapies. We will test an integrated hypothesis that, in the tumor microenvironment, the ISR-driven inactivation of the IFNAR1 pathway in the cytotoxic T lymphocytes plays a pivotal role in tumor growth and progression. Furthermore, efforts to restore IFNAR1 signaling can stimulate anti-cancer immune responses and improve the outcome of therapeutic approaches. To test this hypothesis, we propose to delineate the mechanisms underlying ISR-induced IFNAR1- dependent and independent inactivation of the IFN1 pathway and its role in the loss of viability of intratumoral cytotoxic lymphocytes and the generation of the immune privileged niches (Aim 1). We will also delineate the mechanisms underlying ISR-driven inactivation of the tumoricidal activities of cytotoxic T lymphocytes and determine whether targeting these mechanisms can augment anti-cancer immunity (Aim 2). Completion of these studies should improve our knowledge on the role of ISR in generating the immune privileged niches that provide safe harbor for malignant cells and drive tumor growth and progression. Furthermore, identification and characterization of the mechanisms leading to IFNAR1 pathway inactivation will enable us to identify specific targets for improving the efficacy of anti-cancer immune therapies.

抽象的 尽管1型干扰素细胞因子的抗肿瘤作用，癌症的发展和进展仍会发生 （IFN1，包括IFNα和IFNβ）。 IFN1直接抵消肿瘤的发展和进展（通过抑制 恶性细胞）和间接（通过刺激抗肿瘤免疫力）。我们在过去的资金期间的工作 揭示了肿瘤微环境中诱导的综合应力反应（ISR）有助于恶性和 良性肿瘤细胞逃避IFN1的抗肿瘤效应。我们发现IFN1的ISR驱动灭活 接收器IFNAR1剥夺了肿瘤细胞对IFN1的反应能力，并且在肿瘤生长中起重要作用 和进展。此外，我们的工作揭示了IFNAR1失活的重要作用 激活的肿瘤内细胞毒性T淋巴细胞的死亡，因此在生成免疫特权时死亡 有助于克服抗肿瘤免疫力的利基市场。我们的新试点实验还表明 IFNAR1降低了细胞毒性T淋巴细胞的结核性活性，并破坏了自适应的效率 嵌合抗原受体T细胞和免疫切除点抑制剂的转移。 我们小组和我们的合作者的新初步研究（项目1-2）也表明 促进肿瘤发生的创新机制取决于以某种方式失活的IFNAR1途径 涉及ATF4及其受调节的miRNA（例如miR-211和miR-217），包括对 IFNAR1和IFN刺激基因（IGSS）的mRNA翻译。在我们目前的建议中，我们的目标是 定义这些机制并将其瞄准增加抗癌疗法。我们将测试一个集成的 假设在肿瘤微环境中，ISR驱动的IFNAR1途径的失活 细胞毒性T淋巴细胞在肿瘤生长和进展中起关键作用。此外，努力恢复 IFNAR1信号传导可以刺激抗癌免疫反应并改善治疗的结果 方法。为了检验这一假设，我们建议描述ISR诱导的IFNAR1-的机制 IFN1途径的依赖和独立失活及其在肿瘤内生存力丧失中的作用 细胞毒性淋巴细胞和免疫特权壁ni的产生（AIM 1）。我们还将描绘 ISR驱动的基础机制，使细胞毒性T淋巴细胞的结核病活性和 确定针对这些机制是否可以增强抗癌免疫力（AIM 2）。 这些研究的完成应提高我们对ISR在产生免疫中的作用的知识 为恶性细胞提供安全港并驱动肿瘤生长和进展的特权生态位。 此外，导致IFNAR1途径失活的机制的识别和表征将 使我们能够确定提高抗癌免疫疗法效率的特定目标。