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

• 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
• 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' -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

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.

项目总结/摘要 铂类化疗药物是非小细胞肺癌（NSCLC）的主要治疗方法，但由于其 由于对这些化合物的耐药性普遍存在，PD-1免疫疗法的添加已成为治疗的标准。 在乎然而，化疗已显示通过诱导PD-1表达来影响抗肿瘤免疫， CD 8 + T细胞引发和浸润导致免疫原性细胞死亡。我们迫切需要了解 铂类化疗药物影响免疫应答的分子机制 NSCLC。为了分析铂类化合物对免疫系统的矛盾作用， 与FDA批准的化疗药物具有结构相似性的设计和新型铂化合物库 将用于目的1）在肺癌细胞模型中，研究T细胞活化因子的细胞表面表达模式， 将被审查。基质金属蛋白酶和I类主要组织相容性复合体， 在金属敏感性方面，将在暴露于铂化合物之前和之后进行分析。我们假设 留下铂化合物的配体差异将影响细胞表面上这些因子的水平， 与铂毒性的细胞类型特异性差异相关。目的2）新铂的影响 通过产生肿瘤衍生的前列腺素E2对腺苷依赖性途径的化合物 将测定前列腺素E2（PGE 2）和CD 73的细胞表面表达的调节。我们的假设是 化疗对M-MDSC的间接作用通过以下途径刺激腺苷的产生 步骤：（a）化疗诱导肿瘤细胞中的PGE 2产生;（B）释放的PGE 2上调CD 73外分泌， （c）CD 73催化AMP产生腺苷 （d）腺苷抑制效应CD 8 + T细胞的活化 在肿瘤内。这项提案的长期目标是了解介导铂的机制 耐药性和毒性，最终导致阻断任何免疫抑制作用的策略， 化疗该研究在为阻断免疫系统而提出的信号传导模型方面都是创新的。 系统和设计的铂化合物，只在离开配体变化。