Bioactive Lipid Research Articles

PKC-δ-dependent mitochondrial ROS attenuation is involved as 9-OAHSA combats lipoapotosis in rat hepatocytes induced by palmitic acid and in Syrian hamsters induced by high-fat high-cholesterol high-fructose diet

Metabolic-associated fatty liver disease (MAFLD) is a global concern, often undetected until reaching an advanced stage. Palmitic acid (PA) is a type of fatty acid that increases and leads to liver apoptosis in MAFLD. However, there is currently no approved therapy or compound for MAFLD. Recently, branched fatty acid esters of hydroxy fatty acids (FAHFAs), a group of bioactive lipids, have emerged as promising agents to treat associated metabolic diseases. This study utilizes one type of FAHFA, oleic acid ester of 9-hydroxystearic acid (9-OAHSA), to treat PA-induced lipoapoptosis in an in vitro MAFLD model using rat hepatocytes and a high-fat high-cholesterol high-fructose (HFHCHFruc) diet in Syrian hamsters. The results indicate that 9-OAHSA rescues hepatocytes from PA-induced apoptosis and attenuates lipoapoptosis and dyslipidemia in Syrian hamsters. Additionally, 9-OAHSA decreases the generation of mitochondrial reactive oxygen species (mito-ROS) and stabilizes the mitochondrial membrane potential in hepatocytes. The study also demonstrates that the effect of 9-OAHSA on mito-ROS generation is at least partially mediated by PKC-δ signaling. These findings suggest that 9-OAHSA shows promise as a therapy for MAFLD.

Comprehensive Lipid Profile of Eight Echinoderm Species by RPLC-Triple TOF-MS/MS.

Echinoderms are of broad interest for abundant bioactive lipids. The comprehensive lipid profiles in eight echinoderm species were obtained by UPLC-Triple TOF-MS/MS with characterization and semi-quantitative analysis of 961 lipid molecular species in 14 subclasses of 4 classes. Phospholipids (38.78-76.83%) and glycerolipids (6.85-42.82%) were the main classes in all investigated echinoderm species, with abundant ether phospholipids, whereas the proportion of sphingolipids was higher in sea cucumbers. Two sulfated lipid subclasses were detected in echinoderms for the first time; sterol sulfate was rich in sea cucumbers, whereas sulfoquinovosyldiacylglycerol existed in the sea star and sea urchins. Furthermore, PC(18:1/24:2), PE(16:0/14:0), and TAG(50:1e) could be used as lipid markers to distinguish eight echinoderm species. In this study, the differentiation of eight echinoderms was achieved by lipidomics and revealed the uniqueness of the natural biochemical fingerprints of echinoderms. The findings will help evaluate the nutritional value in the future.

Linking the unfolded protein response to bioactive lipid metabolism and signalling in the cell non-autonomous extracellular communication of ER stress.

The endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER stress and UPR activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non-autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non-autonomous signals to propagate UPR activation in target cells and tissues.

Altered endocannabinoidome bioactive lipid levels accompany reduced DNBS-induced colonic inflammation in germ-free mice

BackgroundGut microbiota are involved in the onset and development of chronic intestinal inflammation. The recently described endocannabinoidome (eCBome), a diverse and complex system of bioactive lipid mediators, has been reported to play a role in various physio-pathological processes such as inflammation, immune responses and energy metabolism. The eCBome and the gut microbiome (miBIome) are closely linked and form the eCBome - miBIome axis, which may be of special relevance to colitis.MethodsColitis was induced in conventionally raised (CR), antibiotic-treated (ABX) and germ-free (GF) mice with dinitrobenzene sulfonic acid (DNBS). Inflammation was assessed by Disease Activity Index (DAI) score, body weight change, colon weight-length ratio, myeloperoxidase (MPO) activity and cytokine gene expression. Colonic eCBome lipid mediator concentrations were measured by HPLC-MS /MS.ResultsGF mice showed increased levels of anti-inflammatory eCBome lipids (LEA, OEA, DHEA and 13- HODE-EA) in the healthy state and higher MPO activity. DNBS elicited reduced inflammation in GF mice, having lower colon weight/length ratios and lower expression levels of Il1b, Il6, Tnfa and neutrophil markers compared to one or both of the other DNBS-treated groups. Il10 expression was also lower and the levels of several N-acyl ethanolamines and 13-HODE-EA levels were higher in DNBS-treated GF mice than in CR and ABX mice. The levels of these eCBome lipids negatively correlated with measures of colitis and inflammation.ConclusionsThese results suggest that the depletion of the gut microbiota and subsequent differential development of the gut immune system in GF mice is followed by a compensatory effect on eCBome lipid mediators, which may explain, in part, the observed lower susceptibility of GF mice to develop DNBS-induced colitis.

Small extracellular vesicles from mesenchymal stromal cells: the next therapeutic paradigm for musculoskeletal disorders

Musculoskeletal disorders are one of the biggest contributors to morbidity and place an enormous burden on the health care system in an aging population. Owing to their immunomodulatory and regenerative properties, mesenchymal stromal/stem cells (MSCs) have demonstrated therapeutic efficacy for treatment of a wide variety of conditions, including musculoskeletal disorders. Although MSCs were originally thought to differentiate and replace injured/diseased tissues, it is now accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly extracellular vesicles (EVs). Endowed with a diverse cargo of bioactive lipids, proteins, nucleic acids and metabolites, MSC-EVs have been shown to elicit diverse cellular responses and interact with many cell types needed in tissue repair. The present review aims to summarize the latest advances in the use of native MSC-EVs for musculoskeletal regeneration, examine the cargo molecules and mechanisms underlying their therapeutic effects, and discuss the progress and challenges in their translation to the clinic.

The insulinotropic activity of oleosomes prepared from various sea buckthorn cultivars in mouse and human pancreatic β cell lines

Sea buckthorn berries contain numerous bioactive lipids such as fatty acids, carotenoids, tocols, and sterols. Among fatty acids, a high concentration of rare in nature palmitoleic acid is characteristic of sea buckthorn pulp oil. We previously showed the potency of pulp oil from the Luczystaja cultivar to augment glucose-induced insulin secretion in pancreatic β cells. Since the composition of sea buckthorn berries varies depending on the cultivar, here we compared the activity of oleosomes from Botaniczeskaja Ljubitelskaja, Golden Rain, Prozracznaja, Maryna and Luczystaja cultivars in two different pancreatic cell lines, a mouse MIN6 and human EndoC-betaH1. Besides the characterization of particle size and ζ-potential, we evaluated the influence of crude and digested oleosomes on cell viability, insulin secretion, and intracellular calcium mobilization. Additionally, the antioxidant activity measured with the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) radical cation-based assay was determined and compared.

Lipoxin A4 (LXA4) Reduces Alkali-Induced Corneal Inflammation and Neovascularization and Upregulates a Repair Transcriptome.

To investigate the anti-inflammatory and anti-angiogenic effects of the bioactive lipid mediator LXA4 on a rat model of severe corneal alkali injury. To induce a corneal alkali injury in the right eyes of anesthetized Sprague Dawley rats. They were injured with a Φ 4 mm filter paper disc soaked in 1 N NaOH placed on the center of the cornea. After injury, the rats were treated topically with LXA4 (65 ng/20 μL) or vehicle three times a day for 14 days. Corneal opacity, neovascularization (NV), and hyphema were recorded and evaluated in a blind manner. Pro-inflammatory cytokine expression and genes involved in cornel repair were assayed by RNA sequencing and capillary Western blot. Cornea cell infiltration and monocytes isolated from the blood were analyzed by immunofluorescence and by flow cytometry. Topical treatment with LXA4 for two weeks significantly reduced corneal opacity, NV, and hyphema compared to the vehicle treatment. RNA-seq and Western blot results showed that LXA4 decreased the gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and pro-angiogenic mediators matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGFA). It also induces genes involved in keratinization and ErbB signaling and downregulates immune pathways to stimulate wound healing. Flow cytometry and immunohistochemistry showed significantly less infiltration of neutrophils in the corneas treated with LXA4 compared to vehicle treatment. It also revealed that LXA4 treatment increases the proportion of type 2 macrophages (M2) compared to M1 in blood-isolated monocytes. LXA4 decreases corneal inflammation and NV induced by a strong alkali burn. Its mechanism of action includes inhibition of inflammatory leukocyte infiltration, reduction in cytokine release, suppression of angiogenic factors, and promotion of corneal repair gene expression and macrophage polarization in blood from alkali burn corneas. LXA4 has potential as a therapeutic candidate for severe corneal chemical injuries.

Targeting Sphingosine 1-Phosphate Metabolism as a Therapeutic Avenue for Prostate Cancer

Prostate cancer (PC) is the second most common cancer in men worldwide. More than 65% of men diagnosed with PC are above 65. Patients with localized PC show high long-term survival, however with the disease progression into a metastatic form, it becomes incurable, even after strong radio- and/or chemotherapy. Sphingosine 1-phosphate (S1P) is a bioactive lipid that participates in all the steps of oncogenesis including tumor cell proliferation, survival, migration, invasion, and metastatic spread. The S1P-producing enzymes sphingosine kinases 1 and 2 (SK1 and SK2), and the S1P degrading enzyme S1P lyase (SPL), have been shown to be highly implicated in the onset, development, and therapy resistance of PC during the last 20 years. In this review, the most important studies demonstrating the role of S1P and S1P metabolic partners in PC are discussed. The different in vitro, ex vivo, and in vivo models of PC that were used to demonstrate the implication of S1P metabolism are especially highlighted. Furthermore, the most efficient molecules targeting S1P metabolism that are under preclinical and clinical development for curing PC are summarized. Finally, the possibility of targeting S1P metabolism alone or combined with other therapies in the foreseeable future as an alternative option for PC patients is discussed. Research Strategy: PubMed from INSB was used for article research. First, key words “prostate & sphingosine” were used and 144 articles were found. We also realized other combinations of key words as “prostate cancer bone metastasis” and “prostate cancer treatment”. We used the most recent reviews to illustrate prostate cancer topic and sphingolipid metabolism overview topic.

S1P/S1PR2 promote pancreatic stellate cell activation and pancreatic fibrosis in chronic pancreatitis by regulating autophagy and the NLRP3 inflammasome

Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that governs various functions by embedding its receptor, S1PR, in different cells. Chronic pancreatitis (CP) is characterized by pancreatic fibrosis via activation of pancreatic stellate cells (PSCs). However, the effect of S1P on CP and PSC activation is still unknown. Here, we conducted a series of experiments to explore the effect of S1P on a CP rat model and primary cultured PSCs. In vivo, CP was induced by intravenous injection of dibutyltin dichloride. S1P was administered at a dosage of 200 μg/kg body weight per day by intraperitoneal injection. After 4 weeks, serum, plasma and pancreas samples were collected for molecular analysis and histological detection. In vitro, PSCs were isolated and cultured for treatment with different doses of S1P. 3MA and MCC950 were used to determine the effect of S1P on PSC activation by regulating autophagy and the NLRP3 inflammasome. JTE013 and Si–S1PR2 were applied to verify that the functions of S1P were realized by combining with S1PR2. Cells were collected for RT‒PCR, western blotting and immunofluorescence. The results showed that S1P was increased in the plasma and pancreatic tissue of CP rats. When S1P was administered to CP rats, the function and histomorphology of the pancreas were severely impaired. In addition, S1P promoted PSC activation, heightened autophagy and enhanced the NLRP3 inflammasome in vivo and in vitro. Moreover, S1PR2 mediated the effect of S1P on PSC activation by regulating autophagy and the NLRP3 inflammasome sequentially. In conclusion, S1P binding to S1PR2 promoted PSC activation and pancreatic fibrosis in CP by regulating autophagy and the NLRP3 inflammasome. These findings provide a theoretical basis for targeting S1P/S1PR2 to treat pancreatic fibrosis and further suggest that considering the role of autophagy and the NLRP3 inflammasome may help with the treatment pancreatic fibrosis.

Functional lipid enriched probiotic cheese: Gastrointestinal stability and potential health benefits

Dairy products are ubiquitous foodstuffs with high consumer acceptance; this facilitates their supplementation with bioactive compounds, such as bioactive lipids. However, their incorporation is limited due to technological challenges and matrix interactions. But what about interactions with probiotics? Thus, this work sought to understand if a probiotic rich cheese fortified with bioactive coconut and avocado oils would be capable of modulating, in vitro, obesity related metabolism. The data showed that, after simulated GIT passage, the oils did not impact the probiotic viable counts and that 50–70% of relevant bioactive fatty acids reached the intestinal phase. Digested fractions also stimulated adipokines production (43–53%), reduced hepatocyte lipidic accumulation (>20%) and increased adipolysis (>50%) and had an anti-inflammatory effect upon macrophages. Based on these results, the proposed solution presented itself as a unique foodstuff capable of being an alternative for the development of a novel line of functional dairy products.

Crosstalk between cannabinoid receptor 2 and lysophosphatidic acid receptor 5

Cannabinoid receptor 2 (CB2) and lysophosphatidic acid receptor 5 (LPA5) are both classified as G-protein coupled receptors (GPCRs) activated by bioactive lipids and are highly expressed in colon cancer cells. However, crosstalk between two receptors and its potential effects on cancer cell physiology have not been fully elucidated. In the present study, the results of bioluminescence resonance energy transfer analysis showed that, among the LPA receptors, CB2 strongly and specifically interacted with LPA5. Both receptors were co-localized in the plasma membrane in the absence of agonists, and the receptors were co-internalized upon activation of either receptor alone or both receptors together. We further investigated the effects of expression of both receptors on cell proliferation and migration, and the molecular mechanisms underlying these effects in HCT116 colon cancer cells. Co-expression of receptors significantly increased cell proliferation and migration by increasing Akt phosphorylation and tumor progression-related gene expression, whereas no such effect was seen upon expression of either receptor alone. These results suggest the possibility of physical and functional crosstalk between CB2 and LPA5.

The Role of Autotaxin and LPA Signaling in Embryonic Development, Pathophysiology and Cancer

Autotaxin (ATX) or Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a secreted enzyme with lysophospholipase D activity, with its primary function being the extracellular hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a bioactive lipid [...].

Potential Benefits of Omega-3 Polyunsaturated Fatty Acids (N3PUFAs) on Cardiovascular Health Associated with COVID-19: An Update for 2023.

The accumulating literature demonstrates that omega-3 polyunsaturated fatty acid (n-3 polyunsaturated fatty acid, N3PUFA) can be incorporated into the phospholipid bilayer of cell membranes in the human body to positively affect the cardiovascular system, including improving epithelial function, decreasing coagulopathy, and attenuating uncontrolled inflammatory responses and oxidative stress. Moreover, it has been proven that the N3PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of some potent endogenous bioactive lipid mediators that mediate some favorable effects attributed to their parent substances. A dose-response relationship between increased EPA and DHA intake and reduced thrombotic outcomes has been reported. The excellent safety profile of dietary N3PUFAs makes them a prospective adjuvant treatment for people exposed to a higher risk of cardiovascular problems associated with COVID-19. This review presented the potential mechanisms that might contribute to the beneficial effects of N3PUFA and the optimal form and dose applied.

Beyond VEGF: Targeting Inflammation and Other Pathways for Treatment of Retinal Disease.

Neovascular eye diseases include conditions such as retinopathy of prematurity, proliferative diabetic retinopathy, and neovascular age-related macular degeneration. Together, they are a major cause of vision loss and blindness worldwide. The current therapeutic mainstay for these diseases is intravitreal injections of biologics targeting vascular endothelial growth factor (VEGF) signaling. Lack of universal response to these anti-VEGF agents coupled with the challenging delivery method underscore a need for new therapeutic targets and agents. In particular, proteins that mediate both inflammatory and proangiogenic signaling are appealing targets for new therapeutic development. Here, we review agents currently in clinical trials and highlight some promising targets in preclinical and early clinical development, focusing on the redox-regulatory transcriptional activator APE1/Ref-1, the bioactive lipid modulator soluble epoxide hydrolase, the transcription factor RUNX1, and others. Small molecules targeting each of these proteins show promise for blocking neovascularization and inflammation. The affected signaling pathways illustrate the potential of new antiangiogenic strategies for posterior ocular disease. SIGNIFICANCE STATEMENT: Discovery and therapeutic targeting of new angiogenesis mediators is necessary to improve treatment of blinding eye diseases like retinopathy of prematurity, diabetic retinopathy, and neovascular age-related macular degeneration. Novel targets undergoing evaluation and drug discovery work include proteins important for both angiogenesis and inflammation signaling, including APE1/Ref-1, soluble epoxide hydrolase, RUNX1, and others.

Altered mucosal and plasma polyunsaturated fatty acids, oxylipins, and endocannabinoids profiles in Crohn’s disease

Selected mucosal and plasma polyunsaturated fatty acids (PUFAs) and related oxylipins and endocannabinoids were determined in 28 Crohn’s disease (CD) patients and 39 controls. Fasting blood and colonic biopsies were collected in all participants, during a disease flare for the patients. Thirty-two lipid mediators including PUFAs, oxylipins, and endocannabinoids were assessed by LC-MS/MS. The pattern of lipid mediators in CD patients is characterized by an increase in arachidonic acid-derived oxylipins and endocannabinoids and a decrease in n-3 PUFAs and related endocannabinoids. A model combining increased 6-epi-lipoxin A4 and 2-arachidonyl glycerol with decreased docoasapentaenoic acid in plasma fairly discriminates patients from controls and may represent a lipidomic signature for CD flare. The study findings suggest that lipid mediators are involved in CD pathophysiology and may serve as biomarkers for disease flare. Further research is required to confirm the role of these bioactive lipids and test their therapeutic potential in CD.

Abstract 240: Bioactive Lipids In Circulation: Biomarker Of Ageing?

Blood transports cells and nutrients. However, it is less known that the major plasma compound is the lipid family in the broad sense. Among these lipids, cholesterol, triglyceride but also the family of polyunsaturated fatty acids (PUFAs) and their metabolites. These lipid mediators are involved in several chronic, inflammatory diseases such as rheumatoid arthritis. But, ageing is associated with chronic inflammation and affects almost 20% of the world’s population. Thus, it is by far the most important population before cardiovascular disease and cancer. Using mass spectrometry analyses, we evaluated the levels of different classes of lipid mediators from healthy young and elderly donors (single donor apheresis). Our data showed a significant decrease of lysophosphatidic acid species‘s expression, modulation of the 5-lipoxygenase product’s, as well as lipid mediators derived from PUFA oxidation. Their effect on blood vessel and circulating cells influenced their function. Indeed, lipid mediator intake is involved in transfusion reactions, and we observed an activation of blood cells, especially platelet, with significant increase of p-selectin. These data highlighted the importance of lipid mediator level in a context of transfusion and ageing of blood donor independently of the storage time of single donor apheresis. They can serve as biomarker of ageing.

Exosomes: Nomenclature, Isolation, and Biological Roles in Liver Diseases.

The biogenesis and biological roles of extracellular vesicles (EVs) in the progression of liver diseases have attracted considerable attention in recent years. EVs are membrane-bound nanosized vesicles found in different types of body fluids and contain various bioactive materials, including proteins, lipids, nucleic acids, and mitochondrial DNA. Based on their origin and biogenesis, EVs can be classified as apoptotic bodies, microvesicles, and exosomes. Among these, exosomes are the smallest EVs (30-150 nm in diameter), which play a significant role in cell-to-cell communication and epigenetic regulation. Moreover, exosomal content analysis can reveal the functional state of the parental cell. Therefore, exosomes can be applied to various purposes, including disease diagnosis and treatment, drug delivery, cell-free vaccines, and regenerative medicine. However, exosome-related research faces two major limitations: isolation of exosomes with high yield and purity and distinction of exosomes from other EVs (especially microvesicles). No standardized exosome isolation method has been established to date; however, various exosome isolation strategies have been proposed to investigate their biological roles. Exosome-mediated intercellular communications are known to be involved in alcoholic liver disease and nonalcoholic fatty liver disease development. Damaged hepatocytes or nonparenchymal cells release large numbers of exosomes that promote the progression of inflammation and fibrogenesis through interactions with neighboring cells. Exosomes are expected to provide insight on the progression of liver disease. Here, we review the biogenesis of exosomes, exosome isolation techniques, and biological roles of exosomes in alcoholic liver disease and nonalcoholic fatty liver disease.

Investigating the lipid-immune signaling axis in modulating the inflammatory response to Salmonella entericaserovar Typhimurium infections

Abstract Salmonella entericaserovar Typhimurium (STM) is an intracellular pathogen that causes gastroenteritis and can disseminate systemically through survival in phagocytes. Eicosanoids-derived bioactive lipids play critical roles in both the induction and resolution of inflammation during bacterial infections or other insults. A subset of these lipids are endogenous ligands for nuclear receptors/transcription factors Peroxisome proliferator-activated receptors (PPAR), which play major roles in fatty acid metabolism and modulation of immune functions (including macrophage MΦ polarization). To elucidate the role of PPARα, we infected streptomycin-pretreated C57BL/6 (wildtype) and Ppara−/−mice with STM (colitis model). We determined that Ppara−/−mice have increased eicosanoid production, decreased inflammatory gene expression and histopathology scores in cecal tissue, and reduced systemic dissemination of bacteria, compared to C57BL/6 mice. These data suggest that the activation of PPARα results in a deleterious immune response favoring STM infection. When polarizing MΦ to various subsets, STM infection enhanced M2b and M2c polarizations (anti-inflammatory and immunoregulatory) in a PPARα-dependent manner. Using liquid chromatography-mass spectrometry (LC/MS), we also determined that STM infection alters the fatty acid profiles in polarized MΦ. Specifically, C57BL/6 M2b-polarized STM-infected MΦ have decreased ceramide levels compared to uninfected control, which would inhibit programmed cell death and enhance bacterial intracellular survival. These findings provide important insights into how the reprogramming of immune metabolism affects host-pathogen interactions during bacterial infections. This work was supported by National Institute of Allergy and Infectious Disease R01 AI168550 (VT)

LPAR5-Mediated Regulation of CD8 T Cell Immunity During Chronic Viral Infections

Abstract Persistent viral infections such as Human Immunodeficiency Virus (HIV), Hepatitis B and C Viruses (HBV & HCV), and Epstein Barr Virus (EBV) result in high mortality rates, tremendous healthcare costs, and limit global life expectancies. Paramount to establishing and maintaining chronic infections, viruses must evade or suppress T cell-mediated immunity, often through promoting the generation of dysfunctional or “exhausted” CD8 T cells. Although there are considerable research efforts investigating mechanisms of T cell exhaustion, further work is necessary to identify and characterize therapeutically targetable regulators of exhaustion programming. Work from our lab has focused on the ability of the bioactive lipid, lysophosphatidic acid (LPA), to regulate CD8 T cell function through LPA receptor 5 (LPAR5) signaling. Importantly, significantly elevated levels of LPA have been identified in chronic viral infections and cancers. We previously demonstrated that activation of LPAR5 on CD8 T cells during TCR engagement suppresses downstream signaling events. Since TCR-induced transcriptional networks regulate T cell exhaustion programming, we hypothesize that LPA-mediated changes in gene expression during chronic infections promotes the generation of dysfunctional CD8 T cells. To investigate the role of LPA in the differentiation of exhausted CD8 T cells, we utilized the LCMV Clone 13 infection model. We postulate that the elevated levels of LPA identified in persistent infections and our initial findings investigating LPAR5 signaling in CD8 T cells provide strong a rationale to evaluate LPA signaling as a previously unexplored pathway by which chronic viruses promote T cell exhaustion to establish and maintain persistence. RO1AI143261-02 T32-AI07405

Endogenously high Omega-3 levels lead to a less suppressive tumor microenvironment

Abstract Cellular transformation leading to cancer development involves multiple changes in the cellular pool of nutrients and macromolecules, including lipids. Tumors switch to the de novo lipid pathway and preferentially accumulate some lipids while excluding others, such as omega-3 (n-3) fatty acids and bioactive lipids derived from them, from the tumor microenvironment. These lipids, known as specialized pro-resolving lipids (SPM), may affect cancer development. Although their roles in decreased cancer risk and overall inflammation are well studied, their effects on anti-tumor immunity are still poorly understood. Here, we report the consequences of high n-3 levels on tumor growth and anti-tumor immunity. We have utilized a FAT-1 transgenic mouse model with an endogenously high n-3: n-6 ratio due to a transgenic enzyme making n-3 fatty acids and EO771 mammary tumor model. Our data show a decreased tumor growth rate in FAT-1 mice associated with increased tumor-infiltrating cells (TILs). In preliminary studies, we further discovered that CD8 and CD4 T-cells in TILs isolated from tumors growing in FAT-1 mice display a more active and proliferative phenotype. Also, the T-cells had decreased exhaustion markers such as TIM-3, LAG-3, and TIGIT in the TILs isolated from tumors growing in FAT-1 animals, and there were fewer FOXP-3 positive T-cells. Together our data suggest a less suppressive anti-tumor immune environment in FAT-1 animals. Currently, we are performing mechanistic studies to understand the role of high omega-3 in the expression and function of these exhaustion markers. We are also exploring the therapeutic benefit of checkpoint inhibitors and cancer vaccines in combination with high omega-3 fatty acids.