Nitric oxide immune dependent resistance mechanisms to anti-PD-1 therapy

一氧化氮免疫依赖性抗 PD-1 疗法的耐药机制

基本信息

批准号：
10214904
负责人：
JOSEPH MARKOWITZ
金额：
$ 24.88万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214904
关键词：
Antigen Presentation Antigen-Presenting Cells Award Basic Science Bioinformatics Biological Response Modifiers Biostatistics Core CD4 Positive T Lymphocytes Cancer Center Cells Cessation of life Clinical Clinical Trials Critical Pathways Cutaneous Melanoma Data Dendritic Cells Development Doctor of Philosophy Ensure Environment Equine mule Event Faculty Failure Flow Cytometry Foundations Generations Human Immune Immune Tolerance Immune checkpoint inhibitor Immune response Immunologic Surveillance Immunology Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Infrastructure Interferon-alpha Interferons Janus kinase Lead Ligands Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Medical Oncologist Melanoma Cell Mentors Mentorship Messenger RNA Methods Modeling Mus Myeloid-derived suppressor cells Nitrates Nitric Oxide Nivolumab Oncologist Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Physicians Population Positioning Attribute Proteins Proteomics Records Regimen Research Research Personnel Resistance STAT protein STAT1 gene Scientist Seasons Series Signal Transduction Specimen Suppressor-Effector T-Lymphocytes T-Cell Receptor T-Lymphocyte Therapeutic Therapeutic Intervention Tissues Toxic effect Translational Research Tumor Immunity Tumor-infiltrating immune cells United States Unresectable Up-Regulation Work anti-CTLA-4 therapy anti-PD-1 anti-PD1 therapy career cost effective therapy experience experimental study improved interest melanoma member nitration nitroaspirin novel therapeutic intervention patient response pembrolizumab programmed cell death ligand 1 programmed cell death protein 1 release factor resistance mechanism response success therapeutic development tool tumor

项目摘要

Project Summary/Abstract I, Joseph Markowitz, MD PhD, am a junior medical oncologist at Moffitt Cancer Center interested in developing immune-based therapeutics for the benefit of melanoma patients. Moffitt is the ideal environment for me to develop into an independent physician scientist given the dedicated Moffitt’s Melanoma and Skin Cancers Center of Excellence, superb flow cytometry core, extensive clinical trial support infrastructure, and highly supportive bioinformatics and biostatistics core. Immune-based therapy has had mounting successes in the past few years with the introduction of checkpoint inhibitors. However, many patients do not respond to therapy, and I intend to dedicate my career into turning these failures into successes. I will have the mentorship to adapt and grow with the project. My mentorship team (Drs. Mulé, Sondak, Conejo-Garcia, Tarhini, and Berglund) was carefully selected to include translational and clinical mentors to ensure that I can mature into a successful immuno- oncologist for therapeutic development in melanoma. Melanoma cells protect themselves from immune attack by releasing factors that stimulate development of immune suppressor cells. Immune suppressor cells, such as myeloid-derived suppressor cells (MDSCs), release large amounts of nitric oxide (NO) that inactivate proteins that normally help immune cells sense and respond to cancer. Hypothesis: Anti-PD-1 resistance in melanoma results, in part, from reduction of DC antigen presentation to T cells via a NO dependent mechanism. Furthermore, NO causes nitration of multiple proteins including STAT1 and NFκB as well as MHC and T-cell receptor (TCR) molecules expressed by immune cells such as dendritic cells (DC), making them less effective for transmitting signals crucial for antigen presentation and rejection of tumors. Therefore, this proposal outlines a series of experiments that will: 1) use murine and ex-vivo models to measure antigen presentation from DC to T cells to elucidate the operative mechanism(s) by which nitration of antigen presentation proteins such as STAT1 results in immune tolerance to melanoma and resistance to anti-PD-1 therapy and to follow the levels of MDSCs, nitric oxide, and nitric oxide producing MDSCs over the course of treatment using multidimensional flow cytometry, and 2) access to well-annotated tissue specimens from melanoma patients receiving anti-PD-1 treatment (unresectable stage III/IV) to quantify the effects of NO and correlate this with changes in immune cell responses to interferon, as well as mRNA and proteomics profiles. Work completed in this proposal will potentially enable the development of new therapeutic strategies to overcome the inhibitory effects of nitric oxide and enhance patient immune responses to melanoma with anti-PD-1 therapy (and potentially other immune- based therapies). In addition, this proposal may lead to new quantitative mass spectrometry and bioinformatics methods to predict who will respond to anti-PD-1 therapy and spare patients from unnecessary toxicity if they are unlikely to respond. The work will also provide me with the necessary research and clinical foundation to become an independent investigator.

项目概要/摘要我，约瑟夫·马科维茨（Joseph Markowitz），医学博士，莫菲特癌症中心的一名初级肿瘤内科医生，对开发感兴趣莫菲特是我的理想环境。凭借专门的莫菲特黑色素瘤和皮肤癌中心，发展成为一名独立的医师科学家卓越、精湛的流式细胞术核心、广泛的临床试验支持基础设施以及高度支持生物信息学和生物统计学核心在过去几年中取得了越来越多的成功。然而，随着检查点抑制剂的引入，许多患者对治疗没有反应，我打算这样做。致力于将这些失败转化为成功，我将获得指导来适应并成长。我的导师团队（Mulé、Sondak、Conejo-Garcia、Tarhini 和 Berglund 博士）对这个项目非常仔细。选择包括转化和临床导师，以确保我能够成熟为一个成功的免疫黑色素瘤细胞保护自身免受免疫攻击的肿瘤学家。通过释放刺激免疫抑制细胞发育的因子，例如免疫抑制细胞。骨髓源性抑制细胞 (MDSC) 释放大量一氧化氮 (NO)，使蛋白质失活通常帮助免疫细胞感知癌症并对其做出反应假设：黑色素瘤中的抗 PD-1 耐药性。部分原因是通过 NO 依赖性机制减少 DC 抗原向 T 细胞的呈递。此外，NO 会引起多种蛋白质的硝化，包括 STAT1 和 NFκB 以及 MHC 和 T 细胞树突状细胞 (DC) 等免疫细胞表达的受体 (TCR) 分子，使其效力降低用于传递对抗原呈递和肿瘤排斥至关重要的信号。因此，该提案概述了这一点。一系列实验将：1）使用小鼠和离体模型来测量从 DC 到 T 细胞阐明抗原呈递蛋白质硝化的操作机制，例如 STAT1 导致对黑色素瘤的免疫耐受和对抗 PD-1 治疗的抵抗，并遵循使用多维流治疗过程中 MDSC、一氧化氮和产生一氧化氮的 MDSC 细胞计数，2) 获取来自接受抗 PD-1 治疗的黑色素瘤患者的注释良好的组织标本治疗（不可切除的 III/IV 期）以量化 NO 的影响并将其与免疫细胞的变化相关联该提案中完成的工作将包括对干扰素的反应以及 mRNA 和蛋白质组学概况。可能有助于开发新的治疗策略来克服一氧化氮的抑制作用并通过抗 PD-1 疗法（以及潜在的其他免疫疗法）增强患者对黑色素瘤的免疫反应此外，该提议可能会带来新的定量质谱和生物信息学。预测谁将对抗 PD-1 治疗产生反应的方法，并避免患者遭受不必要的毒性，如果他们这项工作也将为我提供必要的研究和临床基础。成为一名独立调查员。