Ricciotti Emanuela, Tang Soon Yew, Mrčela Antonijo, Das Ujjalkumar S, Lordan Ronan, Joshi Robin, Ghosh Soumita, Aoyama Justin, McConnell Ryan, Yang Jianing, Grant Gregory R, FitzGerald Garret A
Institute for Translational Medicine and Therapeutics, Perelman School of Medicine.
Department of Systems Pharmacology and Translational Therapeutics.
bioRxiv. 2024 Sep 15:2024.07.02.601762. doi: 10.1101/2024.07.02.601762.
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, 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 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 biosynthesis, reflected by its major urinary metabolite, PGE 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.
靶向程序性细胞死亡蛋白1（PD-1）的免疫检查点抑制剂（ICI）通过恢复受抑制的T细胞细胞毒性反应，彻底改变了癌症治疗方式。然而，对单药ICI的耐药性限制了它们的临床应用。联合策略可增强其抗肿瘤效果，但也可能增加ICI免疫相关不良反应的风险。前列腺素（PG）E由环氧化酶（COX）和微粒体PGE合酶（mPGES-1）依次作用形成，通过其前列素E（EP）受体EPr2和EPr4发挥作用，促进淋巴细胞耗竭，这为ICI揭示了一个额外的靶点。因此，COX抑制剂和EPr4拮抗剂目前正与ICI联合使用，有可能在临床试验中提高抗肿瘤疗效。然而，鉴于COX抑制剂的心血管（CV）毒性，这种联合可能会增加尤其是CV不良事件的风险。在此，我们比较了破坏PGE合成/反应途径的不同方法——mPges-1的整体或骨髓细胞特异性缺失或Epr4的整体缺失——对Pd-1缺陷型高脂血症（Ldlr）小鼠动脉粥样硬化加速形成的影响。所有策略均抑制了动脉粥样硬化的形成。虽然mPGES-1的缺失抑制了PGE生物合成，这由其主要尿代谢产物反映，但在缺乏EPr4的小鼠中PGE生物合成增加，这与主动脉Cox-1和mPges-1的表达增强一致。mPges-1和Epr4的缺失对动脉粥样硬化斑块中免疫细胞群体的影响不同；前者减少了中性粒细胞浸润，而后者抑制了巨噬细胞并增加了T细胞浸润。与这些发现一致，来自Epr4小鼠的骨髓来源巨噬细胞的趋化作用受损。Epr4的缺失还导致髓外淋巴样造血以及脂蛋白脂肪酶活性（LPL）的抑制，并伴有脾肿大、白细胞增多和血脂异常。靶向mPGES-1或EPr4可能抑制淋巴细胞耗竭，同时减轻PD-1阻断导致的CV免疫相关不良事件。
