Eicosanoids in Cancer: New Roles in Immunoregulation

Abstract

Eicosanoids represent a family of active biolipids derived from arachidonic acid primarily through the action of cytosolic phospholipase A2-α. Three major downstream pathways have been defined: the cyclooxygenase (COX) pathway which produces prostaglandins and thromboxanes; the 5-lipoxygenase pathway (5-LO), which produces leukotrienes, lipoxins and hydroxyeicosatetraenoic acids, and the cytochrome P450 pathway which produces epoxygenated fatty acids. In general, these lipid mediators are released and act in an autocrine or paracrine fashion through binding to cell surface receptors. The pattern of eicosanoid production is cell specific, and is determined by cell-specific expression of downstream synthases. Increased eicosanoid production is associated with inflammation and a panel of specific inhibitors have been developed designated non-steroidal anti-inflammatory drugs. In cancer, eicosanoids are produced both by tumor cells as well as cells of the tumor microenvironment. Earlier studies demonstrated that prostaglandin E2, produced through the action of COX-2, promoted cancer cell proliferation and metastasis in multiple cancers. This resulted in the development of COX-2 inhibitors as potential therapeutic agents. However, cardiac toxicities associated with these agents limited their use as therapeutic agents. The advent of immunotherapy, especially the use of immune checkpoint inhibitors has revolutionized cancer treatment in multiple malignancies. However, the majority of patients do not respond to these agents as monotherapy, leading to intense investigation of other pathways mediating immunosuppression in order to develop rational combination therapies. Recent data have indicated that PGE2 has immunosuppressive activity, leading to renewed interest in targeting this pathway. However, little is known regarding the role of other eicosanoids in modulating the tumor microenvironment, and regulating anti-tumor immunity. This article reviews the role of eicosanoids in cancer, with a focus on their role in modulating the tumor microenvironment. While the role of PGE2 will be discussed, data implicating other eicosanoids, especially products produced through the lipoxygenase and cytochrome P450 pathway will be examined. The existence of small molecular inhibitors and activators of eicosanoid pathways such as specific receptor blockers make them attractive candidates for therapeutic trials, especially in combination with novel immunotherapies such as immune checkpoint inhibitors.

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

“…While PGE 2 (together with LXA 4 and PGI 2 ) is hypothesized to be an arachidonic acid-derived pro-resolving mediator [ 199 ], it also shows pro-inflammatory activities such as exacerbating autoimmune diseases [ 208 ]. Moreover, due to its immunosuppressive actions, PGE 2 is considered detrimental in the tumor microenvironment [ 209 , 210 , 211 ]. On one hand levels of PGE 2 were found to be increased in asthma and non-asthmatic eosinophilic bronchitis, while on the other hand, Aggarwal et al reported an inverse relationship between PGE 2 levels and eosinophil sputum counts [ 205 , 206 , 212 ].…”

Vitamin E beyond Its Antioxidant Label

“…The inhibition of COX-2 by γ- and δ-TT attenuated inflammation induced by UVB and γ irradiation [ 118 , 119 ]. Eicosanoids from COXs and 5-LOX pathways contribute to cancer and metastasis development [ 120 ], so, the TF/TT-mediated inhibitory effect on COX-2 and 5-LOX was associated with cancer chemoprevention in chemically-induced/moderate colitis-promoted colon carcinogenesis [ 121 , 122 ] and with decreased ventral prostate epithelial dysplasia in a prostate cancer model induced by N-methyl-N-nitrosourea in rats [ 123 ]. The animal studies investigating the anti-inflammatory effects of vitamin E derivatives are summarized in Table 6 .…”

Ferroptosis-mediated Crosstalk in the Tumor Microenvironment Implicated in Cancer Progression and Therapy

“…In ferroptotic cancer cells, AA can be metabolized to different eicosanoids and their derivatives, such as prostaglandin E2 (PGE2), 15-hydroperoxy-eicosatetra-enoyl-phosphatidylethanolamine (15-HpETE-PE), 15-HETE, 12-HETE, and 5-HETE, through the function of various pathways and released into the tumor immune microenvironment ( Friedmann Angeli et al, 2019 ). PGE2 has been identified as an immunosuppressive factor that suppresses the anti-tumor functions of NK cells, conventional type 1 dendritic cells (cDC1s), and cytotoxic T cells to alter the TME and promote colon cancer cell proliferation, migration and invasion ( Johnson et al, 2020 ). The pro-ferroptotic lipid 15-HpETE-PE that released by ferroptotic cancer cells will induces immune cells undergo ferroptosis in the TME ( Kapralov et al, 2020 ).…”