Atherosclerosis, Prostaglandin Inhibition and Checkpoint Blockade

动脉粥样硬化、前列腺素抑制和检查点封锁

基本信息

批准号：
10304145
负责人：
GARRET A FITZGERALD
金额：
$ 65.41万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304145
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 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

项目摘要

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.

项目摘要靶向编程细胞死亡（PD-1） / pd-ligand1途径的检查点封锁已证明有效通过释放对细胞毒性T淋巴细胞（CTLS）的约束，在一系列癌症中。但是，有一个问题我们是，这种机制可能会易于心血管和自身免疫性疾病。轶事出现了心血管危害的证据，并且绝对数据点已加剧动脉粥样硬化在PD-1删除造成的小鼠中。最近，顺序的前列腺素（PG）E2产生环氧合酶（COX）-2和微粒体PGE合酶的作用，通过其前类样作用（EP）EP2和EP4的受体也已被证明可促进淋巴细胞衰竭。这提高了使用非甾体类抗炎药（NSAID）和检查点抑制剂。但是，仅COX-2抑制就会承认心血管风险，并可能加剧一种因此，检查点封锁。在这里，我们解决了这种可能性，首先寻求建立我们的初步小鼠和人类细胞中的数据似乎在PD-1之间似乎存在双向调节相互作用和PG途径。使用药物和遗传方法，我们将确定是否调制 PGE2改变了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。我们将在小鼠中使用动脉粥样硬化作为人类心血管风险的替代（事实证明是针对NSAIDS，并且与迄今为止相关检查点抑制剂）并确定COX-2的缺失是否会加速并加剧免疫 - 炎症性动脉粥样硬化表型造成PD-1缺失。然后，我们将确定是否 PGE2抑制的替代方法（微粒体PGE合酶的缺失[MPGES] - 1; EP 阻断或抑制任何仅限于髓样细胞的酶）可能会限制或避免加速动脉粥样硬化造成了PD-1的缺失。这些研究将结合PG的差异扰动从接受PD-1封锁的黑色素瘤患者获得的细胞中的途径，新型小鼠模型，状态 ART免疫表型，单细胞转录组学和基于质谱的脂质底物成像以及定义动脉粥样硬化病变的产品分析，以了解结合的潜在严重风险具有检查点抑制剂的NSAID。我们还将探索抑制PGE2的新型替代方法这可能保留抗癌效率，并最大程度地减少组合治疗的心血管风险。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aspirin in Hepatocellular Carcinoma.

DOI：
10.1158/0008-5472.can-21-0758
发表时间：
2021-07-15
期刊：
Cancer research
影响因子：
11.2
作者：
Ricciotti E;Wangensteen KJ;FitzGerald GA
通讯作者：
FitzGerald GA

Endothelial Tenascin-X Is Going With the Flow.

DOI：
10.1161/circresaha.122.321196
发表时间：
2022-05-27
期刊：
CIRCULATION RESEARCH
影响因子：
20.1
作者：
Tang, Soon Yew;FitzGerald, Garret A.
通讯作者：
FitzGerald, Garret A.

The promise and reality of therapeutic discovery from large cohorts.

DOI：
10.1172/jci129196
发表时间：
2020-01
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
E. Melamud;Nick van Bruggen;Garret A. FitzGerald;Claude Bernard;D. L. Taylor;A. Sethi;M. Cule;A. Baryshnikova;D. Saleheen
通讯作者：
E. Melamud;Nick van Bruggen;Garret A. FitzGerald;Claude Bernard;D. L. Taylor;A. Sethi;M. Cule;A. Baryshnikova;D. Saleheen