Imaging Prostate Cancer Immune Evasion using Chemical Exchange Saturation Transfer MRI

对于癌症患者来说，免疫治疗是一种很有前途的策略，特别是对那些对更多的 常规治疗方案。免疫逃避生物标志物的定量成像可以帮助识别 对免疫治疗有反应的患者。化学交换饱和转移磁共振成像 (CEST MRI)是一种分子成像技术，已经被移植到人类身上。CEST磁共振成像有 通过有选择地标记可交换的质子，同时监测多个试剂的独特能力 与射频饱和，这可以被编码为类似于光学方法的“颜色”。我们建议 开发(1)具有独特颜色的试剂和(2)分析方法来量化这些试剂并生成 多色磁共振图像。该奖项将支持Aline Thomas博士向独立研究的过渡 职业生涯。应聘者培训：托马斯博士有生物医学工程背景，研究因素 在使用免疫成分的疾病环境中导致病理生理和再生失败 材料、计算、遗传(治疗基因和报告基因)，并通过合作，常规核磁共振 方法：研究方法。在导师的指导下，托马斯博士将学习如何开发临床可翻译的CEST 药物及其靶点的后处理方法，以探索体内的多种细胞过程 以监测细胞在疾病中的行为和对治疗的反应。她还将接受实践方面的培训 领导研究项目的各个方面--实验室管理、实习生指导、会议演示、 网络和筹款-这对她作为一名独立调查员的成功至关重要 分子成像。拟议的工作将导致编制R01赠款提案。研究计划：A 公认的癌症逃避免疫攻击的机制是谷氨酰胺转运失活(通过PD- L1)，并剥夺渗透免疫细胞的能量(独立于PD-L1)。中心假设是 使用CEST MRI对免疫逃避机制进行定量成像最终可以帮助预测 患者对免疫治疗的反应。托马斯博士建议开发CEST核磁共振试剂和检测 可同时定量谷氨酰胺转运和PD-L1表达的方法。她也会发展成 用后处理方法对这些试剂进行量化。以验证它们作为补充成像的潜力 作为癌症免疫逃逸的生物标记物，她将评估它们在前列腺癌细胞系中的摄取(体外； 癌：PC3、LNCaP、DU-145；非癌：RWPE-1和RWPE-2)和前列腺癌模型(In 体内)，并将其摄取与常规免疫抑制(PD-L1组织学、流式细胞术、 细胞因子)和免疫逃避(表面标记物表达、肿瘤白细胞浸润)指标。目标1： 开发可视化和量化PD-L1在前列腺癌中表达的方法。目标2：制定方法以 前列腺癌中谷氨酰胺转运的可视化和量化。目标3：通过评估这两种方法来验证方法 前列腺癌进展模型中PD-L1表达与谷氨酰胺转运的同步研究

Immunotherapy is a promising strategy for cancer patients, particularly for those nonresponsive to more conventional therapeutic regimens. Quantitative imaging of immune evasion biomarkers can help identify patients responsive to immunotherapy. Chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) is a molecular imaging technology that is already being translated to humans. CEST MRI has the unique ability to monitor multiple agents simultaneously through selectively labeling their exchangeable protons with radiofrequency saturation, which can be encoded as “colors” similar to optical methods. We propose to develop (1) agents with unique colors and (2) analysis methods to quantify these agents and generate multicolor MR images. This award will support Dr. Aline Thomas in her transition to an independent research career. Candidate Training: Dr. Thomas has a background in biomedical engineering, investigating factors contributing to pathophysiology and regeneration failure in disease settings with an immune component using material, computational, genetic (therapeutic and reporter genes), and through collaboration, conventional MRI methods. With the guidance of her mentors, Dr. Thomas will learn how to develop clinically translatable CEST agents and quantify their targets using post-processing methods to probe multiple cellular processes in vivo in order to monitor cell behavior in disease and in response to therapy. She will also be trained in the practical aspects of a leading a research program—lab management, trainee mentorship, conference presentation, networking and fundraising—which are critical to her success as an independent investigator in the field of Molecular Imaging. The proposed work will lead to the preparation of a R01 grant proposal. Research Plan: A recognized mechanism of cancer to evade immunological attack is glutamine transport to deactivate (via PD- L1) and to deprive energy (independent of PD-L1) from infiltrating immune cells. The central hypothesis is that quantitative imaging of immune evasion mechanisms using CEST MRI can ultimately be used to help predict patient response to immunotherapy. Dr. Thomas proposes to develop CEST MRI agents and detection methods that can quantify glutamine transport and PD-L1 expression simultaneously. She will also develop post-processing methods to quantify these agents. To validate their potential as complementary imaging biomarkers of cancer immune evasion, she will evaluate their uptake in prostate cancer cell lines (in vitro; cancerous: PC3, LNCaP, DU-145; noncancerous: RWPE-1 and RWPE-2) and in a prostate tumor model (in vivo) and compare their uptake to conventional immune suppression (PD-L1 histology, flow cytometry, cytokines) and immune evasion (surface marker expression, tumor infiltration of leukocytes) metrics. Aim 1: Develop methods to visualize and quantify PD-L1 expression in prostate cancer. Aim 2: Develop methods to visualize and quantify glutamine transport in prostate cancer. Aim 3: Validate the methods by evaluating both PD-L1 expression and glutamine transport simultaneously in prostate cancer progression models.