Atherosclerosis, Prostaglandin Inhibition and Checkpoint Blockade

项目摘要 针对程序性细胞死亡（PD-1）/PD-配体1通路的检查点阻断已被证明有效 通过释放对细胞毒性T淋巴细胞（CTL）的抑制，在一系列癌症中发挥作用。然而，一个问题是， 这种机制可能会导致心血管和自身免疫性疾病。轶事 心血管危害的证据已经出现，大量数据表明动脉粥样硬化的恶化 在小鼠中，随着Pd-1缺失。最近，前列腺素（PG）E2的产生，通过顺序 环氧合酶（考克斯）-2和微粒体PGE合酶的作用，通过其E前列腺素类发挥作用 (EP)受体EP 2和EP 4也显示促进淋巴细胞耗竭。这就提出了一个 联合使用非甾体抗炎药（NSAID）治疗癌症的可能性， 检查点抑制剂。然而，单独抑制考克斯-2可增加心血管风险，并可能加重心血管风险 由于检查站封锁。在这里，我们解决这种可能性，首先寻求建立在我们的初步 在小鼠和人类细胞中的数据表明，PD-1和PD-L1之间似乎存在双向调节相互作用。 PG途径。使用药理学和遗传学方法，我们将确定是否调节 PGE 2改变淋巴细胞表型和功能以及PD-1的调节如何影响PGE 2 在小鼠和人类细胞中的生物合成反应途径。我们将在小鼠中使用动脉粥样硬化形成作为 人类心血管风险的替代物（因为它被证明是NSAID的替代物，并且因为它与迄今为止的 检查点抑制剂），并确定考克斯-2的缺失是否加速和加剧了免疫- Pd-1缺失导致的炎性动脉粥样硬化表型。然后我们将确定 PGE 2抑制的替代方法（微粒体PGE合酶[mPGES]-1; EP 阻断或抑制任一种酶（仅限于骨髓细胞）可能会限制或避免加速 动脉粥样硬化是Pd-1缺失的结果。这些研究将结合联合收割机的PG微分扰动 从接受PD-1阻断的黑色素瘤患者获得的细胞中的PD-1通路，新的小鼠模型， ART免疫表型分析、单细胞转录组学和基于质谱的脂质组学底物成像 和定义动脉粥样硬化病变的产品分析，以了解合并 NSAID与检查点抑制剂。我们还将探索新的替代方法来抑制PGE 2 这可能保留抗癌功效并使组合疗法的心血管风险最小化。

Project Summary Checkpoint blockade targeting the Programmed cell Death (PD-1) / PD-Ligand1 pathway has proven effective in a range of cancers by releasing a restraint on cytotoxic T lymphocytes (CTLs). However, a concern has been that this very mechanism might predispose to cardiovascular and autoimmune diseases. Anecdotal evidence of a cardiovascular hazard has emerged and abundant data point to exacerbation of atherosclerosis in mice consequent to Pd-1 deletion. Recently, the generation of prostaglandin (PG) E2 by the sequential action of the cyclooxygenase (COX)-2 and microsomal PGE synthase enzymes, acting via its E prostanoid (EP) receptors, EP2 and EP4, has been shown also to promote lymphocyte exhaustion. This raises the possibility of a combinatorial approach to cancer with nonsteroidal anti-inflammatory drugs (NSAIDs) and checkpoint inhibitors. However, COX-2 inhibition alone confers a cardiovascular risk and may exacerbate one consequent to checkpoint blockade. Here, we address this possibility, first seeking to build on our preliminary data in mouse and human cells that there appears to be a bidirectional regulatory interaction between the PD-1 and PG pathways. Using pharmacological and genetic approaches, we will determine whether modulation of PGE2 alters lymphocyte phenotype and function and how regulation of PD-1 may influence the PGE2 biosynthetic response pathway both in mouse and human cells. We will use atherogenesis in the mouse as a surrogate for cardiovascular risk in humans (as it proved to be for NSAIDs and as it correlates to date with checkpoint inhibitors) and determine if deletion of Cox-2 accelerates and exacerbates the immuno- inflammatory atherosclerotic phenotype consequent to Pd-1 deletion. We will then determine whether alternative approaches to PGE2 suppression (deletion of the microsomal PGE Synthase [mPGES] – 1; EP blockade or inhibition of either enzyme restricted to myeloid cells) might limit or avoid the acceleration of atherosclerosis consequent to deletion of Pd-1. These studies will combine differential perturbations of the PG pathway in cells obtained from melanoma patients receiving PD-1 blockade, novel mouse models, state of the art immunophenotyping, single cell transcriptomics and mass-spectrometry based lipidomic substrate imaging and product analysis defining atherosclerotic lesions to understand a potentially serious risk of combining NSAIDs with checkpoint inhibitors. We shall also explore novel alternative approaches to suppressing PGE2 that might conserve the anti-cancer efficacy and minimize the cardiovascular risk of combinatorial therapy.