KY INBRE Admin Supplement: The Role of Platinum Leaving Ligands in Chemo-immunotherapeutic Resistance in Lung Cancer Models

KY INBRE 管理补充：铂离去配体在肺癌模型化疗免疫治疗耐药中的作用

基本信息

批准号：
10399834
负责人：
MARTHA E BICKFORD
金额：
$ 14.88万
依托单位：
UNIVERSITY OF LOUISVILLE
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：
2021-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399834
关键词：
5&apos -Nucleotidase A549 Ablation Acute Adenocarcinoma Adenosine Apoptosis Award Binding CD8-Positive T-Lymphocytes CD8B1 gene Cancer Etiology Cancer Model Cancer Patient Carboplatin Cell model Cell surface Cells Centers of Research Excellence Cessation of life Cisplatin Collaborations DNA Data Development Dinoprostone Disease Progression Enzymes Exposure to FDA approved Fluorescence-Activated Cell Sorting Funding Generations Gifts Goals Hour Human Immune response Immune system Immunosuppression Immunotherapeutic agent Immunotherapy Infiltration Kentucky Lead Ligands Lung Adenocarcinoma MMP9 gene Maintenance Major Histocompatibility Complex Malignant neoplasm of lung Mediating Metalloproteases Metals Modeling Molecular Mus Myeloid Cells Myeloid-derived suppressor cells National Institute of General Medical Sciences Non-Small-Cell Lung Carcinoma Nonmetastatic Nucleosides Pathway interactions Pattern Pharmaceutical Preparations Platinum Platinum Compounds Play Prevalence Production Prostaglandin Production Public Health Resistance Role Scheme Signal Transduction Structure Surface T-Lymphocyte Testing Toxic effect Treatment Failure Tumor Immunity Tumor-Derived United States Universities Variant Work anti-PD-1 anti-PD1 therapy base cancer therapy cell type chemotherapeutic agent chemotherapy cytotoxic design divalent metal effector T cell exhaustion extracellular graduate student immunogenic cell death immunoregulation improved innovation lung cancer cell monocyte neoplastic cell novel novel strategies overexpression oxaliplatin patient derived xenograft model programmed cell death ligand 1 programmed cell death protein 1 response standard of care therapy resistant tool tumor undergraduate student

项目摘要

Project Summary/Abstract Platinum chemotherapeutics are the primary treatment for nonsmall cell lung cancer (NSCLC), but due to the prevalence of resistance to these compounds, the addition of PD-1 immunotherapy has become the standard of care. However, chemotherapy has been shown to impact anti-tumor immunity by inducing PD-1 expression, CD8+ T cell priming, and infiltration leading to immunogenic cell death. There is an urgent need to understand the molecular mechanisms by which platinum-based chemotherapeutics impact the immune response in NSCLC. To analyze the paradoxical effects of platinum compounds on the immune system, a systemically designed and novel bank of platinum compounds with structural similarities to FDA-approved chemotherapeutic will be used. Aim 1) In cellular models of lung cancer, the cell surface expression patterns of T Cell activators will be examined. Both matrix metalloproteases and class I major histocompatibility complex, which play a role in metal sensitivity, will be analyzed before and after exposure to the platinum compounds. We hypothesize that leaving ligand differences of platinum compounds will impact the levels of these factors on the cell surface, correlating to the cell-type-specific variances in platinum toxicity. Aim 2) The impact of the novel platinum compounds on the adenosine dependent pathway through the production of tumor-derived prostaglandin E2 (PGE2) and modulation of the cell surface expression of CD73 will be determined. Our hypothesis is that production of adenosine is stimulated by the indirect effects of chemotherapy on M-MDSCs via the following steps: (a) chemotherapy induces PGE2 production in tumor cells; (b) the released PGE2 upregulates CD73 ecto- 5-nucleotidase enzyme on the surface of M-MDSCs; (c) CD73 catalyzes the production of adenosine from AMP (derived from ATP released by dying cells); and (d) adenosine inhibits the activation of effector CD8+ T cells within the tumors. The long-term goal of this proposal is to understand the mechanisms that mediate platinum resistance and toxicity in NSCLC, ultimately leading to strategies to block any immunosuppressive effects of chemotherapy. The study is innovative in both the signaling model proposed for the blockade of the immune system and in the design of the platinum compounds that vary only at the leaving ligand.

项目摘要/摘要铂化学治疗剂是非小细胞肺癌（NSCLC）的主要治疗方法，但由于对这些化合物的耐药性患病率，PD-1免疫疗法的添加已成为标准关心。然而，化学疗法已被证明会通过诱导的PD-1表达影响抗肿瘤免疫学， CD8+ T细胞启动和浸润导致免疫原性死亡。迫切需要了解铂基化学疗法影响免疫反应的分子机制 NSCLC。分析铂化合物对免疫系统的悖论作用，从系统上设计和新颖的白金化合物库与FDA批准的化学治疗性具有结构相似将使用。目标1）在肺癌的细胞模型中，T细胞活化剂的细胞表面表达模式将被检查。矩阵金属蛋白酶和I类主要的组织相容性复合物都起作用在金属敏感性中，将在暴露于铂化合物之前和之后进行分析。我们假设这一点留下铂化合物的配体差异将影响细胞表面上这些因素的水平，与铂毒性中细胞类型特异性方差相关。目标2）新颖铂的影响通过产生肿瘤衍生的前列腺素E2的腺苷依赖性途径的化合物（PGE2）将确定CD73的细胞表面表达的调节。我们的假设是化学疗法对M-MDSC的间接作用刺激腺苷的产生。步骤：（a）化学疗法在肿瘤细胞中诱导PGE2产生；（b）释放的PGE2上调CD73 ecto- 5M-MDSC表面上的核苷酸酶；（c）CD73催化从AMP产生的腺苷（源自垂死细胞释放的ATP）；（d）腺苷抑制效应子CD8+ T细胞的激活在肿瘤内。该提议的长期目标是了解介导铂的机制 NSCLC的抗性和毒性，最终导致了阻止任何免疫抑制作用的策略化学疗法。这项研究在为免疫块提出的两个信号传导模型中都是创新的系统和在铂化合物的设计中仅在离开配体时变化。