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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：
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
项目类别：
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

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.

项目总结