Disruption of the PGE 2 synthesis / response pathway restrains atherogenesis in programmed cell death-1 (Pd-1) deficient hyperlipidemic mice.

Autor: Ricciotti E; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine.; Department of Systems Pharmacology and Translational Therapeutics., Tang SY; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., Mrčela A; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., Das US; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., Lordan R; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., Joshi R; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., Ghosh S; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., Aoyama J; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., McConnell R; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., Yang J; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine., Grant GR; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine.; Department of Genetics, University of Pennsylvania., FitzGerald GA; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine.; Department of Medicine Perelman School of Medicine, University of Pennsylvania.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 15. Date of Electronic Publication: 2024 Sep 15.
DOI: 10.1101/2024.07.02.601762
Abstrakt: Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) have revolutionized cancer treatment by enabling the restoration of suppressed T-cell cytotoxic responses. However, resistance to single-agent ICIs limits their clinical utility. Combinatorial strategies enhance their antitumor effects, but may also enhance the risk of immune related adverse effects of ICIs. Prostaglandin (PG) E 2 , formed by the sequential action of the cyclooxygenase (COX) and microsomal PGE synthase (mPGES-1) enzymes, acting via its E prostanoid (EP) receptors, EPr2 and EPr4, promotes lymphocyte exhaustion, revealing an additional target for ICIs. Thus, COX inhibitors and EPr4 antagonists are currently being combined with ICIs potentially to enhance antitumor efficacy in clinical trials. However, given the cardiovascular (CV) toxicity of COX inhibitors, such combinations may increase the risk particularly of CV AEs. Here, we compared the impact of distinct approaches to disruption of the PGE 2 synthesis /response pathway - global or myeloid cell specific depletion of mPges-1 or global depletion of Epr4 - on the accelerated atherogenesis in Pd-1 deficient hyperlipidemic (Ldlr -/- ) mice. All strategies restrained the atherogenesis. While depletion of mPGES-1 suppresses PGE 2 biosynthesis, reflected by its major urinary metabolite, PGE 2 biosynthesis was increased in mice lacking EPr4, consistent with enhanced expression of aortic Cox-1 and mPges-1. Deletions of mPges-1 and Epr4 differed in their effects on immune cell populations in atherosclerotic plaques; the former reduced neutrophil infiltration, while the latter restrained macrophages and increased the infiltration of T-cells. Consistent with these findings, chemotaxis by bone-marrow derived macrophages from Epr4 -/- mice was impaired. Epr4 depletion also resulted in extramedullary lymphoid hematopoiesis and inhibition of lipoprotein lipase activity (LPL) with coincident spelenomegaly, leukocytosis and dyslipidemia. Targeting either mPGES-1 or EPr4 may restrain lymphocyte exhaustion while mitigating CV irAEs consequent to PD-1 blockade.
Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.
Databáze: MEDLINE
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