Novel roles of PCSK9 in regulating the tumor immune microenvironment during radiotherapy

PCSK9在放疗过程中调节肿瘤免疫微环境的新作用

• 批准号: 10672976
• 负责人: SCOTT J. ANTONIA
• 金额: $ 52.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672976
• 关键词: Antibodies; Antitumor Response; Binding; Blood; CRISPR/Cas technology; Cholesterol; Clinical; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Cytoplasm; DNA Damage; Data; Distant; Effector Cell; Extravasation; Future; Genomic DNA; Goals; Histocompatibility Antigens Class I; Hyperlipidemia; Immune; Immune response; Immunologic Stimulation; Immunotherapy; Implant; Interferon Type I; Irradiated tumor; Knockout Mice; Local Therapy; Lymphocytic Infiltrate; MHC Class I Genes; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mus; Nature; Neoplasm Transplantation; Nuclear; Outcome; Pathway interactions; Play; Proteins; Publishing; Radiation; Radiation Induced DNA Damage; Radiation induced damage; Radiation therapy; Radiobiology; Reporting; Role; STING agonists; STK11 gene; Signal Pathway; Signal Transduction; Site; Stimulator of Interferon Genes; Stromal Cells; Surface; T-Cell Activation; T-Lymphocyte; Targeted Radiotherapy; Therapy Clinical Trials; Transplantation; Treatment Efficacy; Tumor Immunity; Tumor-infiltrating immune cells; anti-tumor immune response; base; cancer therapy; cell killing; checkpoint therapy; ds-DNA; efficacy evaluation; genetic approach; immune cell infiltrate; immune checkpoint blockade; immunotherapy clinical trials; improved; inhibitor; inhibitor therapy; insight; molecular targeted therapies; mutant; neoplastic cell; novel; pre-clinical; protein expression; radiation effect; response; restraint; subcutaneous; synergism; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY It is now widely recognized that the cGAS-STING pathway plays a critical role in determining the efficacy of radiotherapy. Radiation-induced DNA damage can cause the leakage of nuclear dsDNA fragments into the cytoplasm, activating the cGAS-STING pathway and inducing type I interferons and antitumor immune response. However, the radiation-induced antitumor immune response is self-limiting, with many molecular mechanisms negatively regulating it. Therefore, a better understanding of the suppressive molecular mechanisms is necessary to enhance the beneficial effects of the radiation-induced antitumor immune response. In this project, we intend to study the role of PCSK9, a critical cholesterol-regulating factor, for its role in regulating the antitumor immune response. We base our project on our recently published study that reveals PCSK9’s role in binding and promoting the degradation of MHC class I on the surface of tumor cells, thereby limiting intratumoral T cell activation (Liu et al., Nature, 2020, PMC7770056). We also base our project on our unpublished preliminary data suggesting that inhibiting PCSK9 can significantly enhance the antitumor efficacy of radiotherapy. We will use genetic approaches to study the roles of PCSK9 in regulating tumor growth and the tumor immune microenvironment after radiotherapy in both transplanted and genetically induced autochthonous murine tumor models (Specific Aim 1). We will also use genetic approaches to determine how PCSK9 interacts with the cGAS- STING signaling pathway in regulating tumor growth and the tumor microenvironment after radiotherapy, with a particular emphasis on STK11/LKB1-mutant tumors, which are known to have a suppressed cGAS-STING signaling (Specific Aim 2). Finally, we will also determine if using a clinically approved PCSK9 inhibitor evolocumab can enhance radiotherapy and immune checkpoint blockade (ICB) therapy of locoregional and distant tumors. We expect our results will inform future PCSK9 inhibitor-based radiotherapy and immunotherapy clinical trials upon completing our project.

项目摘要 现在广泛认识到，cGAS-STING途径在确定药物治疗的功效中起关键作用。 放疗辐射诱导的DNA损伤可导致核双链DNA片段渗漏到细胞核中， 细胞质，激活cGAS-STING途径并诱导I型干扰素和抗肿瘤免疫应答。 然而，辐射诱导的抗肿瘤免疫反应是自限性的，有许多分子机制 因此，更好地了解抑制性分子机制是 这是增强辐射诱导的抗肿瘤免疫应答的有益效果所必需的。在这个项目中， 我们打算研究PCSK 9的作用，一个关键的胆固醇调节因子，其在调节抗肿瘤作用中的作用， 免疫反应我们的项目基于我们最近发表的研究，该研究揭示了PCSK 9在结合和 促进肿瘤细胞表面MHC I类分子的降解，从而限制肿瘤内T细胞 激活（Liu等人，Nature，2020，PMC7770056）。我们的项目也基于我们未公布的初步数据 提示抑制PCSK 9可显著增强放疗的抗肿瘤疗效。 我们将利用遗传学方法研究PCSK 9在调节肿瘤生长和肿瘤免疫中的作用。 移植性和遗传诱导的小鼠自体肿瘤放射治疗后的微环境 具体目标（1）。我们还将使用遗传方法来确定PCSK 9如何与cGAS相互作用。 STING信号通路在放疗后调节肿瘤生长和肿瘤微环境中的作用， 特别强调STK 11/LKB 1突变型肿瘤，已知其cGAS-STING抑制 具体目标2（Specific Aim 2）最后，我们还将确定是否使用临床批准的PCSK 9抑制剂 依洛莫司可增强局部和局部免疫检查点阻断（ICB）治疗， 远处肿瘤我们希望我们的研究结果将为未来基于PCSK 9的放射治疗和免疫治疗提供信息。 完成我们的临床试验项目。