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

项目总结 目前，人们普遍认为cGAS-STING通路在决定血管紧张素转换酶的疗效中起着关键作用。 放射治疗。辐射诱导的DNA损伤可导致核dsDNA片段泄漏到 胞质，激活cGAS-STING途径，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的，有许多分子机制。 负向调节它。因此，对抑制分子机制的更好理解是 有必要增强辐射诱导的抗肿瘤免疫反应的有益效果。在这个项目中， 我们打算研究关键的胆固醇调节因子PCSK9在调节抗肿瘤方面的作用。 免疫反应。我们的项目是基于我们最近发表的研究，揭示了PCSK9的S在结合和 促进肿瘤细胞表面MHC-I类分子的降解，从而限制瘤内T细胞 激活(Liu等人，自然，2020，PMC7770056)。我们的项目也是基于我们未公布的初步数据 提示抑制PCSK9可显著增强放射治疗的抗肿瘤效果。 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中的作用 移植性和遗传性小鼠原位肿瘤放射治疗后的微环境 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信号通路在调节放疗后肿瘤生长和微环境中的作用 特别强调STK11/LKB1突变的肿瘤，这些肿瘤已知具有抑制的cGAS-刺痛 发信号(具体目标2)。最后，我们还将确定是否使用临床批准的PCSK9抑制剂 Evocumab可加强局部和局部肿瘤的放疗和免疫检查点阻断(ICB)治疗 远处的肿瘤。我们希望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参考 在完成我们的项目后进行临床试验。

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 We also base our project on our unpublished preliminary data suggesting that inhibiting PCSK9 can significantly enhance the antitumor efficacy of radiotherapy.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.