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

项目摘要/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 对于这些化合物的耐药性的流行，加入PD-1免疫疗法已成为标准 关心。然而，化疗已被证明通过诱导PD-1表达来影响抗肿瘤免疫。 CD8+T细胞的启动和侵袭导致免疫原性细胞死亡。我们迫切需要了解 铂类化疗药物影响小鼠免疫应答的分子机制 非小细胞肺癌。为了分析铂化合物对免疫系统的矛盾影响，系统地 设计和新颖的铂化合物库，结构与FDA批准的化疗药物相似 将会被使用。目的1)在肺癌细胞模型中，T细胞激活剂的细胞表面表达模式 将会被检查。基质金属蛋白酶和I类主要组织相容性复合体都发挥了作用 在金属敏感性方面，将分析暴露于铂化合物前后的情况。我们假设 铂化合物的配基差异会影响细胞表面这些因子的水平， 与铂毒性的细胞类型特定差异相关。目的2)新铂金的影响 腺苷依赖途径上的化合物通过产生肿瘤来源的前列腺素E_2 (PGE2)和对CD73细胞表面表达的调节将被确定。我们的假设是 化疗对M-MDSCs的间接作用通过以下途径刺激腺苷的产生 步骤：(A)化疗诱导肿瘤细胞产生PGE2；(B)释放的PGE2上调CD73外显子- M-MDSCs表面的5-核苷酸酶；(C)CD73催化腺苷的产生 (D)腺苷抑制效应CD8+T细胞的激活 在肿瘤内。这一提议的长期目标是了解调解铂金的机制 NSCLC的耐药性和毒性，最终导致阻止任何免疫抑制作用的策略 化疗。这项研究在两个方面都是创新的，即为阻断免疫而提出的信号模型 体系和铂化合物的设计中，只在离开配体上有所不同。

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.