Project 3- Integrated Stress and Interferon Responses

摘要 尽管1型干扰素细胞因子具有抗肿瘤作用，但仍会发生癌症的发生和发展 (包括干扰素α和干扰素β)。IFN1直接抑制肿瘤的发展和进展(通过抑制 恶性细胞)和间接(通过刺激抗肿瘤免疫)。我们在过去资助期的工作 研究表明，在肿瘤微环境中诱导的整合应激反应(ISR)有助于恶性肿瘤和 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使肿瘤细胞丧失对IFN1的反应能力，在肿瘤生长中发挥重要作用 和进步。此外，我们的工作揭示了IFNAR1失活在ISR诱导的 激活的肿瘤内细胞毒性T淋巴细胞的死亡，并相应地在免疫特许者的产生中 帮助克服抗肿瘤免疫的利基。我们新的试点实验还表明，灭活 IFNAR1降低细胞毒性T淋巴细胞的杀瘤活性并破坏过继免疫的疗效 嵌合抗原受体T细胞和免疫检查点抑制物的转移。 我们团队和我们的合作者(项目1-2)进行的新的初步研究也表明， 促进肿瘤发生的创新机制依赖于IFNAR1通路在某种程度上的失活 涉及ATF4及其调控的miRNAs(例如miR-211和miR-217)，并包括抑制 翻译IFNAR1和干扰素刺激基因(IGSS)的mRNAs。在我们目前的提案中，我们的目标是 定义这些机制，并针对它们来加强抗癌治疗。我们将测试一个集成的 假设，在肿瘤微环境中，ISR驱动的IFNAR1途径在肿瘤中的失活 细胞毒性T淋巴细胞在肿瘤的生长和发展中起着关键作用。此外，恢复 IFNAR1信号通路可激发抗癌免疫反应，改善治疗效果 接近了。为了验证这一假设，我们建议描绘ISR诱导IFNAR1- IFN1通路的依赖和独立失活及其在肿瘤内活性丧失中的作用 细胞毒性淋巴细胞和免疫特免位的产生(目标1)。我们还将划定 ISR诱导的细胞毒性T淋巴细胞杀瘤活性失活的机制 确定靶向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了解 为恶性细胞提供安全庇护所并推动肿瘤生长和进展的特权利基市场。 此外，鉴定和表征导致IFNAR1途径失活的机制将 使我们能够确定特定的目标，以提高抗癌免疫疗法的疗效。

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.