Research Project Cervical Cancer

项目1总结(宫颈) 局部晚期宫颈癌的护理标准(SOC)、盆腔放疗(RT)和同步顺铂、 与30%-50%的失败率有关，而且没有办法治愈复发的疾病。大多数宫颈癌是 由人乳头瘤病毒(HPV)感染引起，HPV癌基因持续表达支持 巨噬细胞介导的一种慢性间质炎症状态。临床前研究表明，肿瘤 相关巨噬细胞(TAMs)是放疗后肿瘤微环境(TME)中含量最丰富的细胞类型 并表现出抑制抗肿瘤免疫发展的“M2样”表型。在我们之前的工作中， 我们证实了宫颈肿瘤18F-脱氧葡萄糖(FDG)摄取对治疗前正电子发射的影响 体层摄影术(PET)与宫颈TME中具有“M2样”表型的TAM增加有关，而且- 用TAMS培养宫颈肿瘤细胞可增加肿瘤细胞对葡萄糖的摄取。我们认为TAMS与肿瘤 TME中的细胞共同进化并相互适应其葡萄糖和ROS代谢，以优化肿瘤生长。在……里面 在这项提议中，我们将检验SOC CRT诱导ROS介导的“代谢开关”这一假设。 每种细胞类型的基因转录和代谢，为限制这种代谢提供了治疗机会 通过促进RT诱导的抗肿瘤免疫来相互依赖并改善SOC CRT后的预后。在这里我们 将结合使用最先进的单细胞和人类肿瘤的空间分辨图谱，以及 ARE成像状态以确定SOC CRT诱导的肿瘤细胞代谢变化的影响 TAM对CRT敏感性的影响，并进行机械性临床前研究，以确定这如何影响 抗肿瘤免疫的研究进展。在目标1中，我们将确定SOC CRT对 宫颈肿瘤细胞的代谢和炎症信号。我们的初步数据支持以CRT为目标 诱导肿瘤细胞SOD2和NRF2表达上调。我们将研究与CRT相关的ROS和 利用肿瘤类器官和新的小鼠模型进行线粒体代谢。在目标2中，我们将确定影响 SOC CRT对和宫颈T细胞表型及功能的影响我们将研究的作用 在小鼠模型中使用新的成像方法、抗体耗竭和CCR2抑制剂进行靶向。在AIM 3中 我们将把PET成像特征的纵向变化与CRT相关的基因表达变化结合起来 以改进患者分类器和响应预测。在这些研究中，我们将使用FDG和64Cu- DOTA-ECLi，一种新的CCR2+TAMS的PET示踪剂最后，我们将与我们培训核心的一名实习生合作， 陨石，从我们的人类数据中优先处理新的线索。这位学员将探索免疫的贡献 添加到SOC CRT时的检查点封锁(ICB)。众所周知，ICB可以改变免疫细胞的新陈代谢， 我们将综合我们的数据和方法来实现我们的最终目标，即将 将免疫代谢转化为新的放射增敏策略。这些实验将优化一种新的治疗方法 联合重编程代谢作为改善SOC CRT+ICB术后预后的新手段。

PROJECT 1 SUMMARY (CERVIX) The standard of care (SOC) for locally advanced cervical cancer, pelvic radiation (RT) with concurrent cisplatin, is associated with a 30-50% failure rate, and there is no cure for recurrent disease. Most cervical cancers are caused by infection with Human Papilloma Virus (HPV), and persistent expression of HPV oncogenes supports a state of chronic stromal inflammation mediated by macrophages. Preclinical studies suggest that tumor associated macrophages (TAMs) are the most abundant cell type in the tumor microenvironment (TME) after RT and exhibit “M2-like” phenotypes that suppress the development of anti-tumor immunity. In our previous work, we demonstrated that cervical tumor 18F-Fluoro-deoxy-glucose (FDG) uptake on pretreatment positron emission tomography (PET) is associated with increased TAMs with “M2-like” phenotypes in the cervix TME, and that co- culture of cervix tumor cells with TAMs increases tumor cell glucose uptake. We propose that TAMs and tumor cells in the TME co-evolve and mutually adapt their glucose and ROS metabolism to optimize tumor growth. In this proposal, we will test the hypothesis that SOC CRT induces ROS-mediated “metabolic switches” that alter gene transcription and metabolism in each cell type, providing a therapeutic opportunity to limit this metabolic co-dependency and improve outcomes after SOC CRT by promoting RT induced anti-tumor immunity. Here we will use a combination of state of the art single cell and spatially resolved profiling of human tumors together with state of the are imaging to determine the impact of SOC CRT induced changes in metabolism in tumor cells and TAMs on CRT sensitivity, and perform mechanistic preclinical studies to determine how this impacts the development of anti-tumor immunity. In Aim 1 we will determine the longitudinal impact of SOC CRT on metabolism and inflammatory signaling in cervix tumor cells. Our preliminary data supports targeting CRT induced upregulation of SOD2 and NRF2 in tumor cells. We will study CRT associated changes in ROS and mitochondrial metabolism using tumor organoids and novel mouse models. In Aim 2 we will determine the impact of SOC CRT on TAM and T cell phenotype and function in the cervix TME. We will study the effect of TAM targeting using novel imaging approaches, antibody depletion and CCR2 inhibitors in mouse models. In Aim 3 we will integrate longitudinal changes in PET imaging features with CRT associated changes in gene expression to improve patient classifiers and response prediction. In these studies, we will use FDG in addition to 64Cu- DOTA-ECLi, a novel PET tracer for CCR2+ TAMs. Finally, we will work with a trainee from our Training Core, METEORITE, to prioritize new leads from our human data. This trainee will explore the contribution of immune checkpoint blockade (ICB) when added to SOC CRT. ICB is well known to alter metabolism in immune cells, and we will synthesize our data and approaches to achieve our ultimate goal which is to incorporate immunometabolism into novel radiosentization strategies. These experiments will optimize a new treatment combination reprogramming TAM metabolism as a novel means to improve outcomes after SOC CRT + ICB.