Project 3- Integrated Stress and Interferon Responses

项目 3 - 综合压力和干扰素反应

• 批准号: 10247664
• 负责人: Serge Y Fuchs
• 金额: $ 29.6万
• 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/10247664
• 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; feasibility testing; 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 型干扰素细胞因子具有抗肿瘤作用，但癌症仍会发生和进展 （IFN1，包括 IFNα 和 IFNβ）直接对抗肿瘤的发生和进展（通过抑制）。 恶性细胞）和间接（通过刺激抗肿瘤免疫力）。 研究表明，肿瘤微环境中诱导的综合应激反应（ISR）有助于恶性和 良性肿瘤细胞逃避 IFN1 的抗肿瘤作用，我们发现 ISR 驱动的 IFN1 失活。 受体IFNAR1剥夺肿瘤细胞对IFN1反应的能力，在肿瘤生长中发挥重要作用 此外，我们的工作揭示了 IFNAR1 失活在 ISR 诱导的过程中的重要作用。 激活的肿瘤内细胞毒性 T 淋巴细胞死亡，并相应地产生免疫特权 我们的新试点实验还表明，有助于克服抗肿瘤免疫的利基。 IFNAR1降低细胞毒性T淋巴细胞的杀肿瘤活性并破坏过继的功效 嵌合抗原受体 T 细胞和免疫检查点抑制剂的转移。 我们小组和合作者的新初步研究（项目 1-2）还表明，额外的 促进肿瘤发生的创新机制依赖于 IFNAR1 通路的失活 涉及 ATF4 及其调节的 miRNA（例如 miR-211 和 miR-217），并包括抑制 IFNAR1 和 IFN 刺激基因 (IGS) 的 mRNA 翻译 在我们当前的提案中，我们的目标是 定义这些机制并将其作为增强抗癌疗法的目标。 假设在肿瘤微环境中，ISR 驱动的 IFNAR1 通路失活 细胞毒性T淋巴细胞在肿瘤的生长和进展中发挥着关键作用。 IFNAR1信号传导可以刺激抗癌免疫反应并改善治疗效果 为了检验这一假设，我们建议描述 ISR 诱导的 IFNAR1- 的潜在机制。 IFN1途径的依赖性和独立失活及其在瘤内细胞活力丧失中的作用 细胞毒性淋巴细胞和免疫特权生态位的产生（目标 1）。 ISR驱动的细胞毒性T淋巴细胞杀肿瘤活性失活的机制 确定针对这些机制是否可以增强抗癌免疫力（目标 2）。 这些研究的完成应该会提高我们对 ISR 在产生免疫中的作用的认识。 特权生态位为恶性细胞提供安全港并推动肿瘤生长和进展。 此外，导致 IFNAR1 通路失活的机制的鉴定和表征将 使我们能够确定提高抗癌免疫疗法疗效的具体目标。