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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要现在人们广泛认识到，cGAS-STING 通路在确定药物疗效方面发挥着关键作用。放射治疗引起的 DNA 损伤可导致核 dsDNA 片段泄漏到细胞核中。细胞质，激活 cGAS-STING 通路并诱导 I 型干扰素和抗肿瘤免疫反应。然而，辐射诱导的抗肿瘤免疫反应是自限性的，具有多种分子机制因此，更好地了解抑制分子机制是必要的。在这个项目中，增强辐射诱导的抗肿瘤免疫反应的有益效果是必要的。我们打算研究PCSK9（一种关键的胆固醇调节因子）在调节抗肿瘤方面的作用我们的项目基于我们最近发表的研究，该研究揭示了 PCSK9 在结合和免疫反应中的作用。促进肿瘤细胞表面MHC I类降解，从而限制瘤内T细胞我们的项目还基于我们未发表的初步数据。提示抑制PCSK9可以显着增强放疗的抗肿瘤疗效。我们将利用遗传学方法研究PCSK9在调节肿瘤生长和肿瘤免疫系统中的作用移植性和遗传诱导的自体鼠肿瘤放疗后的微环境模型（具体目标 1）我们还将使用遗传方法来确定 PCSK9 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的作用特别强调 STK11/LKB1 突变肿瘤，已知此类肿瘤的 cGAS-STING 受到抑制最后，我们还将确定是否使用临床批准的 PCSK9 抑制剂。 evolocumab 可以增强局部和局部放疗和免疫检查点阻断 (ICB) 治疗我们预计我们的结果将为未来基于 PCSK9 抑制剂的放射治疗和免疫治疗提供信息。完成我们的项目后进行临床试验。