Atherosclerosis, Prostaglandin Inhibition and Checkpoint Blockade

动脉粥样硬化、前列腺素抑制和检查点封锁

• 批准号: 10065018
• 负责人: GARRET A FITZGERALD
• 金额: $ 66.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065018
• 关键词: Acceleration; Address; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Attenuated; Autoimmune Diseases; Biochemical; Biological Markers; Blood Vessels; Bone Marrow; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Coculture Techniques; Coxibs; Cytotoxic T-Lymphocytes; Data; Diclofenac; Dinoprostone; Disease; Enzymes; Epoprostenol; Evaluation; Evolution; FDA approved; Fostering; Gene Expression; Generations; Genes; High Fat Diet; Human; Image; Immune; Immune checkpoint inhibitor; Immunophenotyping; In Vitro; Infiltration; Inflammatory; Lesion; Ligands; Lipids; Lymphocyte; Lymphocyte Function; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Lymphoid Cell; Malignant Neoplasms; Mass Spectrum Analysis; Melanoma Cell; Mus; Myeloid Cells; Non-Steroidal Anti-Inflammatory Agents; Outcome; PD-1 blockade; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Phenotype; Plasma; Population; Production; Prostaglandin Inhibition; Prostaglandin Production; Prostaglandins; Prostaglandins I; Regulation; Risk; T-Lymphocyte; Tumor Immunity; Tumor-infiltrating immune cells; Vascular Diseases; Virus; Virus Diseases; WFDC2 gene; anti-PD1 therapy; anti-cancer; atherogenesis; base; cancer therapy; cardioprotection; cardiovascular risk factor; celecoxib; clinical development; clinically relevant; combinatorial; cyclooxygenase 2; cytokine; cytotoxic; exhaust; exhaustion; genetic approach; hazard; immune checkpoint blockade; in vivo; inhibitor/antagonist; innovation; lipidomics; macrophage; melanoma; mouse PGE synthase 1; mouse model; neoplastic cell; novel; programmed cell death protein 1; receptor; response; restraint; sex; stem cells; transcriptomics; tumor

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.

项目概要 针对程序性细胞死亡 (PD-1)/PD-Ligand1 通路的检查点封锁已被证明是有效的 通过释放对细胞毒性 T 淋巴细胞 (CTL) 的限制来治疗一系列癌症。然而，有一个担忧 正是这种机制可能导致心血管和自身免疫疾病。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会加剧 在 Pd-1 缺失后的小鼠中。最近，通过序贯法产生前列腺素（PG）E2 环氧合酶 (COX)-2 和微粒体 PGE 合酶的作用，通过其 E 类前列腺素发挥作用 (EP) 受体 EP2 和 EP4 也被证明可以促进淋巴细胞耗竭。这提高了 与非甾体抗炎药 (NSAID) 联合治疗癌症的可能性 检查点抑制剂。然而，单独抑制 COX-2 会带来心血管风险，并可能加剧心血管风险。 检查站封锁的结果。在这里，我们解决这种可能性，首先寻求建立在我们初步的基础上 小鼠和人类细胞中的数据表明 PD-1 之间似乎存在双向调节相互作用 和 PG 途径。使用药理学和遗传学方法，我们将确定是否调节 PGE2 改变淋巴细胞表型和功能以及 PD-1 的调节如何影响 PGE2 小鼠和人类细胞中的生物合成反应途径。我们将使用小鼠的动脉粥样硬化作为 人类心血管风险的替代指标（已被证明是非甾体抗炎药，并且迄今为止与 检查点抑制剂）并确定 Cox-2 的缺失是否会加速和加剧免疫- Pd-1 缺失导致的炎症性动脉粥样硬化表型。然后我们将确定是否 PGE2 抑制的替代方法（删除微粒体 PGE 合酶 [mPGES] – 1；EP 阻断或抑制仅限于骨髓细胞的任一酶）可能会限制或避免加速 Pd-1 缺失导致动脉粥样硬化。这些研究将结合 PG 的微分扰动 从接受 PD-1 阻断的黑色素瘤患者获得的细胞中的通路、新型小鼠模型、 基于脂质组学底物成像的免疫表型分析、单细胞转录组学和质谱分析 和定义动脉粥样硬化病变的产品分析，以了解组合的潜在严重风险 具有检查点抑制剂的非甾体抗炎药。我们还将探索抑制 PGE2 的新替代方法 这可能会保留组合治疗的抗癌功效并最大限度地降低心血管风险。